Methods for Treating Prostate Cancer

Abstract

The present application relates to a compound of formula (I): TIFF2022553954000031.tif33138 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and n are defined herein. TIFF2022553954000032.tif101152

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority and benefit of U.S. Application No. 63 / 032,453, filed May 29, 2020; U.S. Application No. 63 / 028,843, filed May 22, 2020; U.S. Application No. 62 / 945,418, filed December 9, 2019; and U.S. Application No. 62 / 924,655, filed October 22, 2019, the entire contents of each of which are incorporated herein by reference.

[0002] Field of the Disclosure This application relates to the treatment of prostate cancer, including metastatic and / or castration - resistant prostate cancer, which comprises administering a compound of formula (I) to a subject in need thereof.

Background Art

[0003] Background of the Disclosure The androgen receptor (AR) belongs to the nuclear hormone receptor family that is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782 - 97 (Non - Patent Document 1); Vitam. Horm. 1999, 55:309 - 52 (Non - Patent Document 2)). In the absence of androgens, AR is bound to heat shock protein 90 (Hsp90) in the cytosol. When an androgen binds to AR, its conformation changes, AR is released from Hsp90, and the nuclear localization signal (NLS) is exposed. The latter enables AR to translocate into the nucleus, where AR acts as a transcription factor to promote the expression of genes involved in male sexual characteristics (Endocr. Rev. 1987, 8(1):1 - 28 (Non - Patent Document 3); Mol. Endocrinol. 2002, 16(10), 2181 - 7 (Non - Patent Document 4)). AR deficiency induces androgen insensitivity syndrome, which was previously called testicular feminization.

[0004] AR is involved in the development of male sexual characteristics and has also been well reported to be a cancer gene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276 - 308 (Non - Patent Document 5)). The target gene of AR activity that is generally measured is the secreted prostate - specific antigen (PSA) protein. Current treatment regimens for prostate cancer include inhibition of the androgen - AR axis by two methods. The first method relies on the reduction of androgens, and the second method aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823 - 824 (Non - Patent Document 6)). Despite the development of effective targeted therapies, many patients develop resistance and the disease progresses. Alternative methods for prostate cancer treatment include the removal of AR protein. Since AR is an important inducer of tumor formation in many types of prostate cancer, its elimination should produce a therapeutically beneficial response. There is a continuing need in the art for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy disease. However, for example, transcription factors have non - specific effects and cannot completely target and regulate a specific class of proteins. Therefore, it remains an obstacle to the development of effective anti - cancer agents. Therefore, a "regulatable" small - molecule therapeutic agent that activates or enhances the substrate specificity of cereblon while targeting a wide range of protein species and being specifically regulatable is very useful as a therapeutic agent.

Prior Art Documents

Non - Patent Documents

[0005]

Non - Patent Document 1

Non - Patent Document 2

Non - Patent Document 3

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Summary of the Invention

[0006] In one aspect, the present application is a method for treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I): TIFF0007716396000001.tif33138 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, R 1 is hydrogen, CN, or C1 - C6 alkyl, R 2 is hydrogen, halo, or C1 - C6 alkyl, R 3 is hydrogen or halo, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is CH or N, n is 0 or 1; X 1 , X 2 , X 3 , and X 4 wherein at least two of them are CH, relates to a method.

[0007] In one embodiment, the prostate cancer is castration - resistant prostate cancer.

[0008] In one embodiment, the prostate cancer is metastatic prostate cancer.

[0009] In one embodiment, R 1 is CN, and R 2 is chloro.

[0010] In one embodiment, R 3 is hydrogen.

[0011] In one embodiment, R 3 is fluoro.

[0012] In one embodiment, n is 0.

[0013] In one embodiment, n is 1.

[0014] In one embodiment, each of X 1 , X 2 , X 3 , and X 4 is CH.

[0015] In one embodiment, three of X 1 , X 2 , X 3 , and X 4 are CH, and the others are N.

[0016] In one embodiment, two of X 1 , X 2 , X 3 , and X 4 are CH, and the other two are N.

[0017] In one embodiment, the compound of formula (I) is selected from the group consisting of TIFF0007716396000002.tif129136TIFF0007716396000003.tif151152 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0018] In one embodiment, the compound of formula (I) is orally administered to a subject.

[0019] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once, twice, three times, or four times a day. In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once or divided into two, three, or four times.

[0020] In one embodiment, the therapeutically effective amount of the compound of formula (I) is from about 70 mg to about 1000 mg.

[0021] In one embodiment, the therapeutically effective amount of the compound of formula (I) is from about 100 mg to about 280 mg.

[0022] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a 15-day average AUC greater than about 4,500 ng·h / mL, about 4,600 ng·h / mL, about 4,700 ng·h / mL, about 4,800 ng·h / mL, about 4,900 ng·h / mL, about 5,000 ng·h / mL, about 5,100 ng·h / mL, about 5,200 ng·h / mL, about 5,300 ng·h / mL, 5,400 ng·h / mL, about 5,500 ng·h / mL, about 5,600 ng·h / mL, about 5,700 ng·h / mL, about 5,800 ng·h / mL, about 5,900 ng·h / mL, or about 6,000 ng·h / mL 0-24 to result in.

[0023] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a 15-day average AUC greater than about 4,500 ng·h / mL and less than about 5,500 ng·h / mL 0-24 to result in.

[0024] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a 15-day average C greater than about 300 ng / mL and less than about 400 ng / mL max to result in.

[0025] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 greater than about 330 ng / mL, about 335 ng / mL, about 340 ng / mL, about 345 ng / mL, about 350 ng / mL, about 355 ng / mL, about 360 ng / mL, about 365 ng / mL, about 370 ng / mL, about 375 ng / mL, or about 380 ng / mL. max brings about.

[0026] In one embodiment, the compound of formula (I) is formulated as a tablet. In one embodiment, the tablet comprises the compound of formula (I), and optionally one or more of an emulsifier, surfactant, binder, disintegrant, lubricant, and glidant.

[0027] In one embodiment, the subject in need of treatment is in a fed state.

[0028] In one embodiment, the subject in need of treatment is in a fasting state.

[0029] In one aspect, the present application relates to a method of treating prostate cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of TIFF0007716396000004.tif191137TIFF0007716396000005.tif90151 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0030] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once, or in two, three, or four divided doses.

[0031] In one embodiment, a therapeutically effective amount of the compound of formula (I) is from about 70 mg to about 1000 mg.

[0032] In one embodiment, the compound of formula (I) is formulated as a tablet. [The present invention 1001] A method for treating prostate cancer in a subject in need of treatment for prostate cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I): TIFF0007716396000006.tif33138 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, R 1 is hydrogen, CN, or C 1 ~C 6 alkyl, <{ R 2 is hydrogen, halo, or C 1 ~C 6 alkyl, R 3 is hydrogen or halo, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is CH or N, n is 0 or 1; provided that at least two of X 1 、X 2 、X 3 , and X 4 are CH, and the therapeutically effective amount of the compound of formula (I) is from about 35 mg to about 1000 mg. [The present invention 1002] The method of the present invention 1001, wherein the prostate cancer is castration-resistant prostate cancer. [The present invention 1003] The method of the present invention 1001 or 1002, wherein the prostate cancer is metastatic prostate cancer. [The present invention 1004] R 1 is CN and R 2 is chloro, the method according to any one of the present inventions 1001 to 1003. [The present invention 1005] R Note: There might be an error in the original text where <{ R is an unclosed tag. It's left as is in the translation for consistency with the original.3 is hydrogen, the method according to any one of the present inventions 1001 to 1004. [The present invention 1006] R 3 is fluoro, the method according to any one of the present inventions 1001 to 1004. [The present invention 1007] n is 0, the method according to any one of the present inventions 1001 to 1006. [The present invention 1008] n is 1, the method according to any one of the present inventions 1001 to 1006. [The present invention 1009] X 1 、X 2 、X 3 , and each of X 4 is CH, the method according to any one of the present inventions 1001 to 1008. [The present invention 1010] X 1 、X 2 、X 3 , and three of X 4 are CH and the others are N, the method according to any one of the present inventions 1001 to 1008. [The present invention 1011] X 1 、X 2 、X 3 , and two of X 4 are CH and the other two are N, the method according to any one of the present inventions 1001 to 1008. [The present invention 1012] The compound of formula (I) is TIFF0007716396000007.tif92136TIFF0007716396000008.tif182151 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, the method according to any one of the present inventions 1001 to 1004. [The present invention 1013] The compound of formula (I) is administered orally to the subject, the method according to any one of the present inventions 1001 to 1012. [The present invention 1014] The therapeutically effective amount of the compound of formula (I) is administered to the subject once a day, twice a day, three times a day, or four times a day, the method according to any one of the present inventions 1001 to 1013. [The present invention 1015] Any of the methods of the present invention 1001 - 1014, wherein the therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. [The present invention 1016] Any of the methods of the present invention 1001 - 1013, wherein the therapeutically effective amount of the compound of formula (I) is administered to the subject once, or divided into two, three, or four times. [The present invention 1017] Any of the methods of the present invention 1001 - 1016, wherein the therapeutically effective amount of the compound of formula (I) is from about 70 mg to about 1000 mg. [The present invention 1018] Any of the methods of the present invention 1001 - 1017, wherein the therapeutically effective amount of the compound of formula (I) is from about 100 mg to about 280 mg. [The present invention 1019] Any of the methods of the present invention 1001 - 1018, wherein the therapeutically effective amount of the compound of formula (I) results in a 15 - day mean AUC greater than about 4,500 ng*hr / mL, about 4,600 ng*hr / mL, about 4,700 ng*hr / mL, about 4,800 ng*hr / mL, about 4,900 ng*hr / mL, about 5,000 ng*hr / mL, about 5,100 ng*hr / mL, about 5,200 ng*hr / mL, about 5,300 ng*hr / mL, 5,400 ng*hr / mL, about 5,500 ng*hr / mL, about 5,600 ng*hr / mL, about 5,700 ng*hr / mL, about 5,800 ng*hr / mL, about 5,900 ng*hr / mL, or about 6,000 ng*hr / mL. 0-24 [The present invention 1020] Any of the methods of the present invention 1001 - 1018, wherein the therapeutically effective amount of the compound of formula (I) results in a 15 - day mean AUC greater than about 4,500 ng*hr / mL and less than about 5,500 ng*hr / mL. 0-24 [The present invention 1021] Any of the methods of the present invention 1001 - 1020, wherein the therapeutically effective amount of the compound of formula (I) results in a 15 - day mean C greater than about 300 ng / mL and less than about 400 ng / mL. max [The present invention 1022] Any of the methods of the present invention 1001 - 1021, wherein the therapeutically effective amount of the compound of formula (I) results in a 15 - day mean C greater than about 330 ng / mL, about 335 ng / mL, about 340 ng / mL, about 345 ng / mL, about 350 ng / mL, about 355 ng / mL, about 360 ng / mL, about 365 ng / mL, about 370 ng / mL, about 375 ng / mL, or about 380 ng / mL. max [The present invention 1023] Any method of the present invention from 1001 to 1022, wherein the compound of formula (I) is formulated as a tablet. [The present invention 1024] The method of the present invention 1023, wherein the tablet comprises the compound of formula (I) and optionally one or more of an emulsifier, surfactant, binder, disintegrant, lubricant, and glidant. [The present invention 1025] Any method of the present invention from 1001 to 1024, wherein the subject is in a fed state. [The present invention 1026] Any method of the present invention from 1001 to 1024, wherein the subject is in a fasting state. [The present invention 1027] A method for treating prostate cancer in a subject in need thereof, comprising orally administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof once a day, wherein the compound of formula (I) is TIFF0007716396000009.tif31132TIFF0007716396000010.tif219151TIFF0007716396000011.tif28135 selected from the group consisting of or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof. [The present invention 1028] The method of the present invention 1027, wherein the therapeutically effective amount of the compound of formula (I) is administered to the subject once, or divided into two, three, or four times. [The present invention 1029] The method of the present invention 1027 or 1028, wherein the therapeutically effective amount of the compound of formula (I) is about 70 mg to about 1000 mg. [The present invention 1030] Any method of the present invention from 1027 to 1029, wherein the compound of formula (I) is formulated as a tablet.

Brief Description of the Drawings

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[0046] Detailed Description Definitions "Halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0047] "C1-C6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 6 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0048] As used herein with respect to a compound of formula (I), "pharmaceutically acceptable salts" means salt forms of the compound of formula (I) and hydrates of salt forms in which one or more water molecules are present. Such salts and hydrated forms retain the biological activity of the compound of formula (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, acetates, anthronates (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, butyrates, calcium, calcium edetate, cancillarates, carbonates, chlorides, citrates, clavulariates, dihydrochlorides, edetates, edisylicates, estrates, esylates, fumarates, gluceptates, gluconates, glutamates, glycolylarsanilates, hexafluorophosphates, hexylresorcinates, hydrabamine, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, magnesium, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucates, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoates, oleates, oxalates, palmitates, pamoates (1,1-methan-bis-2-hydroxy-3-naphthoate, einbonate), pantothenates, phosphoric / diphosphoric acids, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicyclates, slamate, tannates, tartrates, theocrylates, tosylates, triethiodides, and valerates, including both water-soluble salts and water-insoluble salts.

[0049] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in the constitution (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the salts of the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0050] The compounds of formula (I) can exist, for example, in non-solvated and solvated forms such as hydrates.

[0051] "Solvate" means a solvate addition form containing either a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in the crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H2O, and such combinations can form more than one hydrate. In hydrates, the water molecules are bonded via secondary valences by intermolecular forces, especially hydrogen bridges. Solid hydrates contain water in a stoichiometric ratio as so-called water of crystallization, and the water molecules do not have to be equivalent with respect to their bonding state. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Similarly, hydrates of the salts of the compounds of the present invention are also suitable.

[0052] When a compound crystallizes from a solution or slurry, it can crystallize in different lattice arrangements in space (this property is called polymorphism), forming crystals with different crystal morphologies, each of which is known as a "polymorph". As used herein, "polymorph" refers to a crystalline form of a compound of formula (I), where the molecules are located at three-dimensional lattice sites. Different polymorphs of the compound of formula (I) may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal morphology, packing mode, flowability and / or solid state stability.

[0053] As referred to herein, an "isotope derivative" relates to a compound of formula (I) that is isotopically enriched or labeled with one or more stable isotopes (with respect to one or more atoms of the compound). Thus, in the present application, the compounds of formula (I) include compounds that are isotopically enriched or labeled with one or more atoms such as deuterium, for example.

[0054] The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of formula (I) that is suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic reactions, etc. within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio, and effective for its intended use, and is, if possible, the zwitterionic form of the compound of the present invention.

[0055] As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to yield any compound detailed by the formulas of the present invention. Various forms of prodrugs are known in the art and are discussed, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development” Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975) and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug and Prodrug Metabolism: Chemistry, Biochemistry And Enzymology” John Wiley and Sons, Ltd. (2002).

[0056] The present invention also encompasses pharmaceutical compositions containing pharmaceutically acceptable prodrugs of the compounds of the present invention, and methods of treating a disorder by administering a pharmaceutically acceptable prodrug of the compounds of the present invention. For example, compounds of the present invention having a free amino group, amide group, hydroxy group or carboxylic acid group can be converted to prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino group, hydroxy group, or carboxylic acid group of a compound of the present invention by an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, a free carboxyl group can be derivatized as an amide or an alkyl ester. A free hydroxy group can be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groups also include carbonate prodrugs, sulfonic acid esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, and the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functional groups, or the acyl group may be an amino acid ester as described above. This type of prodrug is described in J.Med.Chem.1996,39,10. A free amine can also be derivatized as an amide, sulfonamide, or phosphonamide.All of these prodrug moieties may incorporate groups containing, but not limited to, ether, amine, and carboxylic acid functional groups. The combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds.

[0057] Metastatic prostate cancer or metastasis refers to prostate cancer that has spread beyond the prostate to other parts of the body, such as bone, bone, lymph nodes, liver, lung, brain, etc.

[0058] Castrate-resistant prostate cancer or castration-resistant prostate cancer (or castrate-resistant or castration-resistant prostate cancer) is a type of prostate cancer that continues to grow even when the amount of testosterone in the body has decreased to a very low level.

[0059] Metastatic castrate-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 decreased to a very low level.

[0060] As used herein, "treatment" refers to the management and care of a subject to fight a disease, condition, or disorder, and includes the reduction or alleviation of symptoms or complications, or the elimination of the disease, condition, or disorder.

[0061] As used herein, "prevention" refers to stopping the onset of symptoms or complications of a disease, condition, or disorder.

[0062] "Administration" refers to introducing an agent such as a compound of formula (I) to a subject. Related terms "administer" and "administration of" (and grammatical equivalents) refer to both direct administration, which can be administration to a subject by a healthcare provider or self-administration by the subject, and / or indirect administration, which can be the act of prescribing an agent. For example, a physician who instructs a patient to self-administer an agent and / or provides a prescription drug to the patient for the agent is administering the agent to the patient.

[0063] As used herein, "therapeutically effective amount" means the amount of the free base of a compound of formula (I) that is sufficient to treat, ameliorate, or prevent a particular disease (e.g., prostate cancer), a symptom of a disease, a disorder, or a condition, or to exert a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The effective amount for a particular subject can depend on the subject's weight, size and health, the nature and extent of the condition, and whether additional therapeutic agents are administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0064] As used herein, "C max " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administration of a dose of that compound to the subject.

[0065] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to the subject compound 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 (ng×H / mL).

[0066] As used herein, "AUC tau " refers to the AUC from 0 hours to the end of the dosing interval.

[0067] "AUC 0-24 " means the AUC from 0 hours to 24 hours after administration of a single dose.

[0068] As used herein with respect to the oral dosage forms of the present disclosure, "sustained release" or "CR" means that the compound of formula (I) is released from the dosage form according to a predetermined profile, which profile may include when, where release occurs, and / or a specified release rate over a specified period after oral administration.

[0069] As used herein with respect to the oral dosage forms of the present disclosure, "sustained release agent" refers to one or more substances or materials that regulate the release of the compound of formula (I) from the dosage form. The sustained release agent can be an organic or inorganic, natural or synthetic material, such as a polymeric material, a triglyceride, a derivative of a triglyceride, a fatty acid and a salt of a fatty acid, talc, boric acid, and colloidal silica.

[0070] 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 formula (I) and remains substantially intact in the acidic environment of the stomach but dissolves in the pH environment of the intestine.

[0071] As applied to the CR oral dosage forms described herein, "gastric resistance" or "GR" means that the release of the compound of formula (I) in the stomach of a subject does not exceed 5%, 2.5%, 1% or 0.5% of the total amount of the compound of formula (I) in the dosage form.

[0072] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specific amount (dose) of the compound of formula (I) as an active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and an inactive ingredient (excipient), and formulated into a specific configuration suitable for oral administration and drug delivery, such as a tablet or a capsule. In one embodiment, the composition is in the form of a tablet that can be scored.

[0073] As used herein, the term "carrier" includes carriers, excipients, and diluents, and refers to a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, composition, or vehicle that is involved in the conveyance or transport of a pharmaceutical from one organ or part of the body of a subject to another organ or part of the body.

[0074] Abiraterone acetate is a commercially available agent for the treatment of metastatic castration-resistant prostate cancer developed by Janssen and sold under the brand name Zytiga®.

[0075] The term "about" as part of a quantitative expression such as "about X" includes any value that is 10% higher or lower than X, and also includes any numerical value between X - 10% and X + 10%. Thus, for example, a weight of about 40 g includes weights from 36 to 44 g.

[0076] "Comprising" or "comprises" as applied to a particular dosage form, composition, use, method, or process described or claimed herein means that the dosage form, composition, use, method, or process includes all of the elements recited in a particular description or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, use, or process excludes other materials or steps that do not substantially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic effect of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" mean the exclusion of trace amounts of other components and anything in excess of substantial method or process steps.

[0077] As used herein to describe a subject, "fasting condition" or "fasting state" means that the subject has not consumed a meal for at least 4 hours prior to the point of interest, such as the time of administration of the compound of formula (I). In one embodiment, the subject in a fasting state has not consumed a meal for at least 6, 8, 10, or 12 hours prior to administration of the compound of formula (I).

[0078] As used herein to describe a subject, "fed condition" or "fed state" means that the subject has consumed a meal within less than 4 hours prior to the point of interest, such as the time of administration of the compound of formula (I). In one embodiment, the subject in a fed state has not consumed a meal for at least 3, 2, 1, or 0.5 hours prior to administration of the compound of formula (I).

[0079] The articles "a" and "an" are used herein for grammatical purposes to refer to one or more than one (i.e., at least one) of the article's object. By way of example, "an element" means one element or more than one element.

[0080] The term "and / or" is used herein to mean either "and" or "or" unless otherwise indicated.

[0081] The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or macaque.

[0082] In one embodiment, the subject is a human.

[0083] In one embodiment, the subject is a human diagnosed with prostate cancer.

[0084] In one embodiment, the subject is a human diagnosed with metastatic prostate cancer.

[0085] In one embodiment, the subject is a human diagnosed with castration-resistant prostate cancer.

[0086] In one embodiment, the subject is a human diagnosed with metastatic castration-resistant prostate cancer.

[0087] The compound of formula (I) In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering a compound of formula (I) to a subject in need thereof. In one aspect, the present application relates to the use of a compound of formula (I) in the treatment and / or prevention of prostate cancer. In one aspect, the present application relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment and / or prevention of prostate cancer.

[0088] As referred to herein, the compound of formula (I) is a compound having the following structure: TIFF0007716396000012.tif33134 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, R 1 is hydrogen, CN, or C1-C6 alkyl, R 2 is hydrogen, halo, or C1-C6 alkyl, R 3 is hydrogen or halo, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is CH or N, n is 0 or 1.

[0089] In one embodiment, R 1 is hydrogen.

[0090] In one embodiment, R 1 is CN.

[0091] In one embodiment, R 1 is C1-C6 alkyl.

[0092] In one embodiment, R 2 is hydrogen.

[0093] In one embodiment, R 2 is halo. In one embodiment, R 2 is F. In one embodiment, R 2 is Cl. In one embodiment, R 2 is Br. In one embodiment, R 2 is I.

[0094] In one embodiment, R 2 is C1-C6 alkyl.

[0095] In one embodiment, R 3 is hydrogen.

[0096] In one embodiment, R 3 is halo. In one embodiment, R 3 is F. In one embodiment, R 3 is Cl. In one embodiment, R 3 is Br. In one embodiment, R 3 is I.

[0097] In one embodiment, at least one of X 1 , X 2 , X 3 , and X 4 is CH.

[0098] In one embodiment, at least two of X 1 , X 2 , X 3 , and X 4 are CH.

[0099] In one embodiment, X 1 , X 2 , X 3 , and X 4At least three of them are CH.

[0100] In one embodiment, X 1 、X 2 、X 3 、and X 4 are each CH.

[0101] In one embodiment, X 1 、X 2 、and X 3 are each CH, and X 4 is N.

[0102] In one embodiment, X 1 、X 2 and X 4 are each CH, and X 3 is N.

[0103] In one embodiment, X 1 、X 3 、and X 4 are each CH, and X 2 is N.

[0104] In one embodiment, X 2 、X 3 、and X 4 are each CH, and X 1 is N.

[0105] In one embodiment, X 1 and X 2 are each CH, and X 3 and X 4 are each N.

[0106] In one embodiment, X 1 and X 3 are each CH, and X 2 and X 4 are each N.

[0107] In one embodiment, X 1 and X 4 are each CH, and X 2and X 3 is N respectively.

[0108] In one embodiment, X 2 and X 3 are CH respectively, and X 1 and X 4 are N respectively.

[0109] In one embodiment, X 2 and X 4 are CH respectively, and X 1 and X 3 are N respectively.

[0110] In one embodiment, X 3 and X 4 are CH respectively, and X 1 and X 2 are N respectively.

[0111] In one embodiment, n is 0.

[0112] In one embodiment, n is 1.

[0113] In one embodiment, the compound of formula (I) is TIFF0007716396000013.tif92136TIFF0007716396000014.tif182151 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0114] In one embodiment, the compound of formula (I) is a compound of formula (I-a): TIFF0007716396000015.tif31138 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0115] In one embodiment, the compound of formula (I) is a compound of formula (I-b): TIFF0007716396000016.tif28141 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0116] In one embodiment, the compound of formula (I) is a compound of formula (I-c): TIFF0007716396000017.tif28140 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0117] In one embodiment, the compound of formula (I) is a compound of formula (I-d): TIFF0007716396000018.tif28140 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0118] In one embodiment, the compound of formula (I) is a compound of formula (I-e): TIFF0007716396000019.tif28140 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0119] In one embodiment, the compound of formula (I) is a compound of formula (I-f): TIFF0007716396000020.tif27141 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0120] In one embodiment, the compound of formula (I) is a compound of formula (I-g): TIFF0007716396000021.tif28141 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0121] In one embodiment, the compound of formula (I) is a compound of formula (I-h): TIFF0007716396000022.tif28141 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0122] In one embodiment, the compound of formula (I) is a compound of formula (I-i): TIFF0007716396000023.tif28140 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0123] The compounds of formula (I) can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and the conversion and manipulation of functional groups, including the use of protecting groups, as can be obtained from relevant scientific literature in the field or standard reference textbooks in the field. Without limitation to any one or several sources, recognized reference textbooks on organic synthesis include Smith, M.B.; Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001, and Greene, T.W.; Wuts, P.G.M. Protective Groups in OrganicSynthesis, 3 rd ed.; John Wiley & Sons: New York, 1999. Methods for preparing the compounds of formula (I) are described in U.S. Patent Application Publication No. 2018 / 0099940, current U.S. Patent No. 10,584,101, the contents of which are incorporated herein by reference in their entirety.

[0124] Method for ubiquitinating / degrading a target protein in a cell The present invention provides a method for ubiquitinating / degrading a target protein in a cell. The method involves administering a bifunctional compound comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker portion, as described elsewhere herein. The E3 ubiquitin ligase binding moiety is bound to the protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the target protein moiety recognizes the target protein. Degradation of the target protein occurs when the target protein is placed in proximity to the ubiquitin ligase, resulting in a decrease / inhibition of the action of the target protein and control of the protein level. The control of the protein level brought about by the present invention provides treatment of a medical condition or disorder, which is mediated via the target protein by reducing the level of that protein in the patient's cells.

[0125] In one embodiment, the present invention relates to a method of treating a patient in need of modulating a medical condition or disorder by a protein when degradation of the protein produces a therapeutic effect in the patient. The method involves administering to a patient in need thereof an effective amount of a compound according to the present invention, optionally in combination with another bioactive agent (e.g., abiraterone). The medical condition or disorder may be a disease caused by a microorganism or another foreign entity such as a virus, bacterium, fungus, protozoan or other microorganism, or may be a medical condition caused by overexpression of a protein in which the medical condition and / or disorder occurs.

[0126] Treatment method In one aspect, the present application relates to a method of treating and / or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0127] The methods of treating cancer described herein include reducing tumor size. As another method, or additionally, the cancer is metastatic cancer, and the treatment method includes inhibiting metastatic cancer cell infiltration.

[0128] In one embodiment, the cancer is prostate cancer.

[0129] In one embodiment, the cancer is metastatic prostate cancer.

[0130] In one embodiment, the cancer is castration-resistant prostate cancer.

[0131] In one embodiment, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0132] In one embodiment, a subject suffering from mCRPC will have a different response to treatment with a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, depending on the subject's AR biomarker status.

[0133] In one aspect, the present application relates to treating prostate cancer with a compound of formula (I), the compound of formula (I) being a compound having the following structure: TIFF0007716396000024.tif33137 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , and X 4 and n are as defined herein. In one embodiment, the cancer is metastatic prostate cancer. In one embodiment, the cancer is castration-resistant or castration-resistant prostate cancer. In one embodiment, the cancer is metastatic castration-resistant prostate cancer.

[0134] In one aspect, the present application relates to treating prostate cancer with a compound of formula (I), the compound of formula (I) being selected from the group consisting of TIFF0007716396000025.tif129136 TIFF0007716396000026.tif151151 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof. In one embodiment, the cancer is metastatic prostate cancer. In one embodiment, the prostate cancer is castration-resistant or castration-resistant prostate cancer. In one embodiment, the prostate cancer is metastatic castration-resistant prostate cancer.

[0135] In one aspect, the present application relates to treating prostate cancer with a compound of formula (I) in combination with another bioactive agent, the compound of formula (I) being a compound having the following structure: TIFF0007716396000027.tif33137 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , and X 4 as well as n are defined herein. In one embodiment, the compound of formula (I) is a compound of formula (I-g).

[0136] In one embodiment, the prostate cancer treated with the combination of the compound of formula (I) and another bioactive agent is metastatic prostate cancer. In one embodiment, the prostate cancer treated with the combination of the compound of formula (I) and another bioactive agent is castration-resistant or castration-resistant prostate cancer. In one embodiment, the prostate cancer treated with the combination of the compound of formula (I) and another bioactive agent is metastatic castration-resistant prostate cancer. In one embodiment, the other bioactive agent is abiraterone or a pharmaceutically acceptable salt thereof. In one embodiment, the other bioactive agent is abiraterone acetate.

[0137] In one aspect, the treatment of cancer results in a reduction in the size of the tumor. The reduction in the size of the tumor may also be referred to as "tumor regression". Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment, more preferably the tumor size is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably 75% or more. The size of the tumor may be measured by any reproducible measuring means. In a preferred aspect, the size of the tumor may be measured as the diameter of the tumor.

[0138] In another aspect, the treatment of cancer results in a reduction in the tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its size before treatment, more preferably the tumor volume is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably 75% or more. The tumor volume may be measured by any reproducible measuring means.

[0139] In another aspect, the treatment of cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to its number before treatment, more preferably the number of tumors is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably 75% or more. The number of tumors may be measured by any reproducible measuring means. In a preferred aspect, the number of tumors may be measured by counting the tumors that can be seen with the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0140] In another aspect, the treatment of cancer results in a decrease in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by at least 5% relative to that number prior to treatment, more preferably the number of metastatic lesions is reduced by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, even more preferably by at least 50%, and most preferably by at least 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. In a preferred embodiment, 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 embodiment, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0141] In another aspect, the treatment of cancer results in an increase in the mean survival time of the population of treated subjects as compared to a population administered the carrier alone. Preferably, the mean survival time is increased by more than 30 days, more preferably by more than 60 days, 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 may be measured by any reproducible means. In a preferred embodiment, the increase in the mean survival time of the population may be measured, for example, by calculating the mean length of survival after initiation of treatment with the active agent or compound for the population. In another preferred embodiment, the increase in the mean survival time of the population may be measured, for example, by calculating the mean length of survival after completion of primary treatment with the active agent or compound for the population.

[0142] In another aspect, the treatment of cancer results in an increase in the average survival period of the treated population of subjects as compared to the untreated population of subjects. Preferably, the average survival period increases by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival period of the population may be measured by any reproducible means. In a preferred aspect, the increase in the average survival period of the population may be measured, for example, by calculating the average length of survival after the start of treatment with an active agent or compound for the population. In another preferred aspect, the increase in the average survival period of the population may also be measured, for example, by calculating the average length of survival after the completion of primary treatment with a compound of formula (I) for the population.

[0143] In another aspect, the treatment of cancer results in a decrease in the tumor growth rate. Preferably, after treatment, the tumor growth rate decreases by at least 5% relative to the pre-treatment figure, more preferably the tumor growth rate decreases 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 may be measured by any reproducible measurement means. In a preferred aspect, the tumor growth rate is measured according to the change in tumor diameter per unit time.

[0144] In another aspect, the treatment of cancer results in a decrease in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%, more preferably tumor regrowth is 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 may be measured by any reproducible measurement means. In a preferred aspect, tumor regrowth is measured, for example, by measuring the increase in tumor diameter from post-treatment tumor shrinkage. In another preferred aspect, the decrease in tumor regrowth is indicated by the failure of the tumor to recur after treatment has stopped.

[0145] The dosage of the compound of formula (I) for any of the methods and uses described herein will vary depending, among other factors, on the drug, the age, weight, and clinical condition of the recipient subject, and other factors that influence the selected dosage, and in particular on the experience and judgment of the clinician or practitioner administering the therapy.

[0146] A therapeutically effective amount of the compound of formula (I) can be administered one or more times a day for up to 30 days or more, followed by one or more days without administration of the compound of formula (I). This type of treatment schedule, i.e., consecutive daily administration of the compound of formula (I) followed by consecutive daily non - administration of the compound of formula (I), may be referred to as a treatment cycle. The treatment cycle can be repeated as many times as necessary to achieve the intended effect.

[0147] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered in a single dose or divided doses once, twice, three times, four times, or more than four times a day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 days continuously, or for a period of 2 months, 3 months, 4 months, 5 months, 6 months, or longer, and 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, 235, 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, 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,It is 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.

[0148] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more times per day, in a single dose or divided doses, and 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, 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, 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, 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, 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 (the dosage can be adjusted according to the patient's body weight (kg), body surface area (m, 2 ) and age (years)).

[0149] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 35 mg to about 1,000 mg, administered once, twice, three times, four times, or more times a day, in single or divided doses (this dosage can be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and age (years)).

[0150] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 70 mg to about 1,000 mg, administered once, twice, three times, four times, or more times a day, in single or divided doses (this dosage can be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and age (years)).

[0151] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 35 mg, 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, administered once, twice, three times, four times, or more times a day, in single or divided doses (this dosage can be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and age (years)).

[0152] The therapeutically effective amount of the compound of formula (I) may also be in the range of about 0.01 mg / kg per day to about 100 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.05 mg / kg per day to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.075 mg / kg per day to about 5 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.10 mg / kg per day to about 1 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0153] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0154] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0155] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0156] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. In one embodiment, this daily dose of the compound of formula (I) may be administered to the subject all at once. In one embodiment, this daily dose of the compound of formula (I) may be administered to the subject in two divided doses. In one embodiment, this daily dose of the compound of formula (I) may be administered to the subject in three divided doses. In one embodiment, this daily dose of the compound of formula (I) may be administered to the subject in four divided doses. In one embodiment, this daily dose of the compound of formula (I) may be administered to the subject in five or more divided doses. In one embodiment, these divided administrations 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.

[0157] In one embodiment, a therapeutically effective amount of the compound of formula (I) is about 3,500 ng*hr / mL, about 3,550 ng*hr / mL, about 3,600 ng*hr / mL, about 3,650 ng*hr / mL, about 3,700 ng*hr / mL, about 3,750 ng*hr / mL, about 3,800 ng*hr / mL, about 3,850 ng*hr / mL, about 3,900 ng*hr / mL, about 3,950 ng*hr / mL, about 4,000 ng*hr / mL, 4,050 ng*hr / mL, about 4,100 ng*hr / mL, about 4,150 ng*hr / mL, about 4,200 ng*hr / mL, 4,250 ng*hr / mL, about 4,300 ng*hr / mL, about 4,350 ng*hr / mL, about 4,400 ng*hr / mL, about 4,450 ng*hr / mL, about 4,500 ng*hr / mL, about 4,550 ng*hr / mL, about 4,600 ng*hr / mL, about 4,650 ng*hr / mL, about 4,700 ng*hr / mL, about 4,750 ng*hr / mL, about 4,800 ng*hr / mL, about 4,850 ng*hr / mL, about 4,900 ng*hr / mL, about 4,950 ng*hr / mL, about 5,000 ng*hr / mL, 5,050 ng*hr / mL, about 5,100 ng*hr / mL, about 5,150 ng*hr / mL, about 5,200 ng*hr / mL, about 5,250 ng*hr / mL, about 5,300 ng*hr / mL, about 5,350 ng*hr / mL, about 5,400 ng*hr / mL, about 5,450 ng*hr / mL, about 5,500 ng*hr / mL, about 5,550 ng*hr / mL, about 5,600 ng*hr / mL, about 5,650 ng*hr / mL, about 5,700 ng*hr / mL, about 5,750 ng*hr / mL, about 5,800 ng*hr / mL, about 5,850 ng*hr / mL, about 5,900 ng*hr / mL, 5,950 ng*hr / mL, or about 6,000 ng*hr / mL, 6,050 ng*hr / mL, about 6,100 ng*hr / mL, about 6,150 ng*hr / mL, about 6,200 ng*hr / mL, about 6,250 ng*hr / mL, about 6,300 ng*hr / mL, about 6,350 ng*hr / mL, about 6,400 ng*hr / mL, about 6,450 ng*hr / mL, about 6,500 ng*hr / mL, about 6,550 ng*hr / mL, about 6,600 ng*hr / mL, about 6,650 ng*hr / mL, about 6,700 ng*hr / mL, about 6,750 ng*hr / mL, about 6,800 ng*hr / mL, about 6,850 ng*hr / mL, about 6,900 ng*hr / mL, 6,950 ng*hr / mL or about 7,000 ng*hr / mL, 7,050 ng*hr / mL, about 7,100 ng*hr / mL, about 7,150 ng*hr / mL, about 7,200 ng*hr / mL, about 7,250 ng*hr / mL, about 7,300 ng*hr / mL, about 7,350 ng*hr / mL, about 7,400 ng*hr / mL, about 7,450 ng*hr / mL, about 7,500 ng*hr / mL, about 7,550 ng*hr / mL, about 7,600 ng*hr / mL, about 7,650 ng*hr / mL, about 7,700 ng*hr / mL, about 7,750 ng*hr / mL, about 7,800 ng*hr / mL, about 7,850 ng*hr / mL, about 7,900 ng*hr / mL, 7,950 ng*hr / mL, or about 8,000 ng*hr / mL, 8,050 ng*hr / mL, about 8,100 ng*hr / mL, about 8,150 ng*hr / mL, about 8,200 ng*hr / mL, about 8,250 ng*hr / mL, about 8,300 ng*hr / mL, about 8,350 ng*hr / mL, about 8,400 ng*hr / mL, about 8,450 ng*hr / mL, about 8,500 ng*hr / mL, about 8,550 ng*hr / mL, about 8,600 ng*hr / mL, about 8,650 ng*hr / mL, about 8,700 ng*hr / mL, about 8,750 ng*hr / mL, about 8,800 ng*hr / mL, about 8,850 ng*hr / mL, about 8,900 ng*hr / mL, 8,950 ng*hr / mL, or greater than about 9,000 ng*hr / mL of the mean AUC on day 15, 0-24 results in.

[0158] In one embodiment, a therapeutically effective amount of a compound of formula (I) provides a 15-day average C greater than about 250 ng / mL, about 255 ng / mL, about 260 ng / mL, about 265 ng / mL, about 270 ng / mL, about 275 ng / mL, about 280 ng / mL, about 285 ng / mL, about 290 ng / mL, about 295 ng / mL, about 300 ng / mL, about 305 ng / mL, about 310 ng / mL, about 315 ng / mL, about 320 ng / mL, about 325 ng / mL, about 330 ng / mL, about 335 ng / mL, about 340 ng / mL, about 345 ng / mL, about 350 ng / mL, about 355 ng / mL, about 360 ng / mL, about 365 ng / mL, about 370 ng / mL, about 375 ng / mL, about 380 ng / mL, about 385 ng / mL, about 390 ng / mL, about 395 ng / mL, about 400 ng / mL, about 405 ng / mL, about 410 ng / mL, about 415 ng / mL, about 420 ng / mL, about 425 ng / mL, about 430 ng / mL, about 435 ng / mL, about 440 ng / mL, about 445 ng / mL, about 450 ng / mL, about 455 ng / mL, about 460 ng / mL, about 465 ng / mL, about 470 ng / mL, about 475 ng / mL, about 480 ng / mL, about 485 ng / mL, about 490 ng / mL, about 495 ng / mL, or about 500 ng / mL. max results in.

[0159] A therapeutically effective amount of a compound of formula (I) can first be estimated in either cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful dosages and routes for administration in humans. Therapeutic / preventive effects, and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (the therapeutically effective dose in 50% of the population) and LD 50 (the lethal dose for 50% of the population). The dose ratio between toxicity and therapeutic effect is an index of therapy, LD 50 / ED 50It can be expressed as a ratio. A pharmaceutical composition showing a large therapeutic index is preferred. The dosage can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0160] The dosage and administration are adjusted to provide a sufficient level of the compound of formula (I) 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, the time and frequency of administration, drug combinations, response sensitivity, and tolerance / response to therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, weekly, or every 2 weeks depending on the half-life and clearance rate of the particular formulation.

[0161] In one embodiment, for a method of treating prostate cancer by combining a compound of formula (I) with another bioactive agent, a therapeutically effective amount of the compound of formula (I) is described herein, and the therapeutically effective amount of the other bioactive 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, 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, 235, 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, 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 is administered once, twice, three times, four times, or more than four times a day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or for 2, 3, 4, 5, 6 months, or for a longer period, in a single or divided dose. In one embodiment, the other bioactive agent is abiraterone or a pharmaceutically acceptable salt thereof. In one embodiment, the other bioactive agent is abiraterone acetate.,

[0162] In one embodiment, for a method of treating prostate cancer with a combination of a compound of formula (I) and abiraterone or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of the compound of formula (I) is described herein, and the therapeutically effective amount of abiraterone 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, 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, 235, 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, 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 is administered once, twice, three times, four times, or more than four times a day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 days continuously, or for 2, 3, 4, 5, 6 months, or for a longer period, in single or divided doses. In one embodiment, abiraterone is abiraterone acetate.,

[0163] In one embodiment, for a method of treating prostate cancer with a combination of a compound of formula (I) and abiraterone acetate, a therapeutically effective amount of the compound of formula (I) is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg, administered once a day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 days, or for a longer period continuously, in single or divided oral doses. In one embodiment, abiraterone acetate is administered orally twice a day in combination with 5 mg of prednisone. In one embodiment, the combination of the compound of formula (I) and abiraterone acetate is administered to a subject in a fasting state who requires it. In one embodiment, the subject has not eaten at least 2 hours before and at least 1 hour after administration of the combination of the compound of formula (I) and abiraterone acetate.,

[0164] In one embodiment, the compound of formula (I) and abiraterone acetate are administered to the subject simultaneously. In one embodiment, the compound of formula (I) and abiraterone acetate are administered to the subject continuously.,

[0165] In one embodiment, the compound of formula (I) and abiraterone acetate are administered to a subject with temporal proximity.

[0166] In some embodiments, "temporal proximity" means that the compound of formula (I) is administered within a period before or after the administration of abiraterone acetate such that the therapeutic effect of the compound of formula (I) overlaps with the therapeutic effect of abiraterone acetate. In some embodiments, the therapeutic effect of the compound of formula (I) completely overlaps with the therapeutic effect of abiraterone acetate. In some embodiments, "temporal proximity" means that the compound of formula (I) is administered within a period before or after the administration of abiraterone acetate such that there is a synergistic effect between the compound of formula (I) and abiraterone acetate.

[0167] "Temporal proximity" can vary depending on various factors including, but not limited to, the age, sex, weight, genetic background, health status, medical history and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition being treated or alleviated; the therapeutic outcome to be achieved; the dosage, frequency of administration and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporally close" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be performed in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0168] Pharmaceutical composition In one embodiment, the compound of formula (I) is formulated for oral administration. For example, in one embodiment, the compound of formula (I) is formulated as a tablet comprising 0, 1, 2 or more of an emulsifier, surfactant, binder, disintegrant, lubricant and glidant.

[0169] In one embodiment, the emulsifier is hypromellose.

[0170] In one embodiment, the surfactant is vitamin E polyethylene glycol succinate.

[0171] In one embodiment, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0172] In one embodiment, the disintegrant is croscarmellose sodium.

[0173] In one embodiment, the lubricant refers to a substance used to promote powder flow by reducing interparticle aggregation. In one embodiment, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of silicon dioxide, anhydrous silica colloids, starch, and talc.

[0174] In one embodiment, the lubricant refers to a substance that prevents components from sticking and / or aggregating in the machines used in the preparation of the dosage forms of the present disclosure. In one embodiment, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and vegetable stearin.

[0175] The pharmaceutical composition containing the compound of formula (I) can be produced in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, wet grinding, emulsifying, encapsulating, enclosing, or freeze-drying processes. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate processing the compound of formula (I) into a preparation that can be pharmaceutically used. Of course, the appropriate formulation depends on the selected route of administration.

[0176] A pharmaceutical composition suitable for injection comprises a sterile aqueous solution (in the case of water solubility) or dispersion for immediate preparation of a sterile injectable solution or dispersion, and a sterile powder. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that it is readily injectable. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include in the composition isotonic agents such as sugars, polyalcohols such as mannitol, sorbitol, etc., and sodium chloride. Prolongation of the absorption of the injectable composition can be brought about, for example, by including in the composition agents that delay absorption such as aluminum monostearate and gelatin.

[0177] A sterile injectable solution can be prepared by incorporating a compound of formula (I) in a suitable solvent with one or a combination of the ingredients listed above in the required amounts and, if necessary, then filter sterilizing. Generally, a dispersion is prepared by incorporating the active agent or compound in a sterile vehicle containing a basic dispersion medium and the other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and lyophilization, which yield a powder of the active ingredient and any additional desired ingredients from its previously sterile filtered solution.

[0178] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable carrier for food use. They may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds of formula (I) can be used in the form of tablets, lozenges or capsules in combination with excipients. Oral compositions can also be prepared using a fluid carrier for use as a mouse wash, where the agent or compound in the fluid carrier is applied orally, rinsed in the mouth and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant substances can be included as part of the composition. Tablets, pills, capsules, lozenges, etc., can contain the following components: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, sodium starch glycolate (Primogel®) or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavoring, or any of the compounds of similar nature.

[0179] For administration by inhalation, the agent or compound is delivered in the form of an aerosol spray from a pressurized container or dispenser or nebulizer containing a suitable propellant, such as a gas like carbon dioxide.

[0180] Systemic administration can also be by transmucosal means or transdermal means. For transmucosal administration or transdermal administration, suitable penetrants for the permeated barrier are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into ointments, salves, gels or creams generally known in the art.

[0181] In one aspect, the compound of formula (I) is prepared with a pharmaceutically acceptable carrier that protects the drug or compound from rapid elimination from the body, such as controlled release formulations including, for example, implants and microencapsulation delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0182] Liposome suspensions (including liposomes targeted to infected cells having 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, such as those described in U.S. Patent No. 4,522,811.

[0183] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unit doses for the subject to be treated, each unit containing a predetermined quantity of the active agent or compound calculated to produce the desired therapeutic effect in association with a given pharmaceutically carrier. The specification of the unit dosage forms of the present application is determined by and directly depends on the unique properties of the compound of formula (I) and the particular therapeutic effect to be achieved.

[0184] The pharmaceutical composition can be contained in a container, pack, or dispenser together with instructions for administration.

[0185] Exemplary modes of administration of the compound of formula (I) include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, is administered orally. In one embodiment, the compound of formula (I) is administered as tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, or pellets.

[0186] Exemplary pharmaceutical compositions are tablets and gelatin capsules containing salts of the compounds of formula (I) and pharmaceutically acceptable carriers, for example, a) diluents such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, such as 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, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants such as silica, talcum, stearic acid, magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets, also c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta lactose, corn sweeteners, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, and optionally, d) disintegrants such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or foaming mixtures, e) absorbents, colorants, flavorants and sweeteners, f) emulsifiers or dispersants such as Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafil, Labrafac, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelsire, Vitamin E TGPS or other acceptable emulsifiers, and / or g) agents that enhance the absorption of salts such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200.

[0187] For preparing a pharmaceutical composition from a compound of formula (I) or any salt or hydrate thereof, the inert pharmaceutically acceptable carrier may be either solid or liquid. Preparations in solid form include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may consist of from about 5 to about 95% 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 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.

[0188] Preparations in liquid form include solutions, suspensions and emulsions. For example, addition of sweetening and opacifying agents for oral solutions, suspensions, and emulsions, or water or water-propylene glycol solutions for parenteral injection. Liquid form preparations may also include solutions for nasal administration.

[0189] Particularly for injectable, liquid compositions can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed salts are dissolved or mixed with pharmaceutically acceptable solvents such as water, physiological saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles or serum proteins can be used to solubilize the disclosed compounds.

[0190] Parenteral injectable administration is commonly used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or in solid form, suitable for dissolution in a liquid prior to injection.

[0191] Aerosol preparations suitable for inhalation may contain solids in solution and powder form, which may be in combination with a pharmaceutically acceptable carrier such as an inert compressed gas, for example nitrogen.

[0192] Also included are solid form preparations which are intended to be converted into a liquid form preparation for either oral or parenteral administration immediately prior to use. Such liquid forms include solutions, suspensions, and emulsions.

[0193] Depending on the intended method of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms such as, for example, for injection, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., and sometimes in unit doses, in accordance with conventional pharmaceutical practice. Similarly, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all of which can be administered using forms well known to those skilled in the pharmaceutical arts.

[0194] The pharmaceutical compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90% or from about 1% to about 20% of the salts of the present disclosure by weight or volume.

[0195] All amounts of any component of the oral dosage forms described herein, for example tablets, expressed on a % w / w basis, refer to the total weight of the oral dosage form unless otherwise indicated.

Examples

[0196] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit of the specific procedures described herein. Of course, the examples are provided to illustrate a particular embodiment and are not intended to limit the scope of the present disclosure. It should be further understood that one may have means for various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the appended claims.

[0197] Example 1 - In Vitro Study Using Compound (I-G) Compound (I-g) has been shown to degrade 95% - 98% of the androgen receptor (AR) in multiple cell lines typically used in prostate cancer research, including, for example, VCaP cells. (DC of Compound (I-g) in VCaP 50 is 1 nM.) Near-maximal degradation was observed within 4 hours of administration of Compound (I-g). Compound (I-g) inhibits VCaP proliferation approximately 60-fold more potently than enzalutamide. (Figure 1)

[0198] Figure 2 shows the decrease in AR in VCaP tumor cells in response to treatment with Compound (I-g) at concentrations of 0.03 nM, 0.1 nM, 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, and 300 nM.

[0199] Example 2 - In Vivo Test Using Animals and Evaluation of the Preclinical Efficacy Exposure Range for Compound (I-G) In a VCaP xenograft animal model, a preclinical animal study was conducted using Compound (I-g). VCaP was derived from the metastatic growth of prostate cancer in the spine. This is a desirable cell line for in vivo testing as it exhibits many of the characteristics of clinical prostate cancer. VCaP is also a useful model for studying AR resistance as it expresses an AR splice variant that has been shown to promote resistance to AR antagonists. (European Urology. April 2018;73(4):572 - 582)

[0200] Once-daily oral administration of compound (I-g) at doses of 0.1 mg / kg (mpk), 0.3 mg / kg, 1 mg / kg, and 3 mg / kg was performed in a castrated VCaP xenograft model (Figure 3). Enzalutamide (20 mg / kg) and vehicle were also used as control groups.

[0201] Once-daily oral administration of compound (I-g) at doses of 1 mg / kg, 3 mg / kg, and 10 mg / kg was performed in an intact (non-castrated) VCaP xenograft model (Figure 4). Enzalutamide (20 mg / kg) and vehicle were also used as control groups.

[0202] Once-daily oral administration of compound (I-g) at doses of 3 mg / kg and 10 mg / kg was performed in an enzalutamide-resistant VCaP xenograft model (Figure 5). Enzalutamide (20 mg / kg) and vehicle were also used as control groups.

[0203] The pharmacokinetic results of once-daily oral administration of compound (I-g) at doses of 1 mg / kg and 3 mg / kg are shown in Table 1 below. The dose of 1 mg / kg of compound (I-g) is the lowest dose that is superior to enzalutamide in VCaP xenografts. The dose of 3 mg / kg of compound (I-g) was the minimum effective dose in an enzalutamide-resistant VCaP model (70% tumor growth inhibition compared to the control group).

[0204] Figure 6 shows the decrease in AR in enzalutamide-resistant VCaP tumors in response to administration of compound (I-g) at 10 mg / kg and 3 mg / kg (oral, once-daily).

[0205] [Table 1] Values represent total drug concentration. † AUC or area under the curve is a measure of total exposure. ‡ C maxis the measured peak concentration during the dosing period.

[0206] Example 3 - In Vivo Animal Study Using Compound (I-g) and Abiraterone The combination of compound (I-g) and abiraterone significantly attenuated tumor growth in castrated VCaP xenografts compared to either agent alone.

[0207] Example 4 - Toxicity Study Animals were orally administered compound (I-g) once daily for 28 days, after which the high-dose animals had a 14-day recovery period.

[0208] In dogs, oral administration of compound (I-g) at 3 mg / kg, 10 mg / kg, or 30 mg / kg once daily was performed. A dose of 30 mg / kg was determined to exceed the maximum tolerated dose. Gastrointestinal changes were observed at all dose levels (including vehicle alone). Reversible elevations of hepatic function enzymes that were not considered harmful were observed in some mid- and high-dose animals. Male animals showed a decrease in prostate weight, which may be due to the pharmacology of compound (I-g).

[0209] In male rats, oral administration of compound (I-g) at 20 mg / kg, 60 mg / kg, or 120 mg / kg once daily was performed. In female rats, oral administration of compound (I-g) at 20 mg / kg, 40 mg / kg, or 120 mg / kg once daily was performed.

[0210] Overall, compound (I-g) was well tolerated at all doses except for the 80 mg / kg female cohort. These rats lost weight and had a decreased food consumption. All findings in male high-dose rats were completely reversible (hepatic hypertrophy, thickening of the femoral epiphyseal cartilage). Male rats showed a decrease in prostate weight, which may be due to the pharmacology of compound (I-g).

[0211] Example 5 - Phase I Clinical Trial Study Design Using Compound (I-g) A Phase I clinical trial using compound (I-G) was conducted. A conventional 3+3 dose escalation design was implemented. The starting dose of compound (I-g) was 35 mg once daily orally with food. Dose escalation was dependent on toxicity.

[0212] The primary criteria for this trial were men with metastatic castration-resistant prostate cancer (mCRPC), at least two prior systemic therapies, at least one of which was abiraterone or enzalutamide, and disease progression on the most recent therapy (e.g., rising PSA or two or more new lesions on a bone scan).

[0213] The primary objective of this trial was to obtain the maximum tolerated dose of compound (I-g) and the recommended Phase II trial dose. Additional objectives included the evaluation of the overall safety of compound (I-g), pharmacokinetics, antitumor activity (e.g., PSA, RECIST), and biomarkers, including, for example, AR degradation in CTCs and AR degradation by comparison of pre-treatment versus post-treatment biopsies (if available), AR (and other) gene mutations in ctDNA, and AR-V7 in CTCs.

[0214] Example 6 - Phase I Pharmacokinetic Data - Oral Administration of Compound (I-g) In the Phase I clinical trial, compound (I-g) was administered orally at doses of 35 mg / day, 70 mg / day, and 140 mg / day. Treatment with 140 mg / day of compound (I-g) was observed to enter the preclinical effective range related to tumor growth inhibition.

[0215] The initial pharmacokinetic results are shown in Table 2 and Figure 7 below, which represent the mean concentrations of compound (I-g) for all three tested doses (35 mg / day, 70 mg / day, and 140 mg / day) over a 24-hour period after dosing on Day 15.

[0216]

Table 2

[0217] Example 7 - Phase I Dose Escalation Study Using Compound (I - g) Compound (I - g) was orally administered to human subjects at doses of 35 mg / day, 70 mg / day, 140 mg / day and 280 mg / day (n = 22).

[0218] In the 35 mg / day cohort (n = 3), dose - limiting toxicity was not observed and no grade 2, 3 or 4 adverse events were observed.

[0219] In the 70 mg / day cohort (n = 4), dose - limiting toxicity was not observed. One patient experienced grade 2 adverse events (diarrhea, fatigue, vomiting). One patient experienced a grade 3 adverse event (anemia) not related to the administration of compound (I - g).

[0220] In the 140 mg / day cohort (n = 8), dose - limiting toxicity was not observed. 50% of the patients experienced grade 2 adverse events and one patient experienced a grade 3 adverse event (decrease in lymphocyte count). These results do not include one patient who was judged unevaluable in this cohort group and whose treatment was discontinued on day 1.

[0221] In the 280 mg / day cohort (n = 7), one patient experienced dose - limiting toxicity and renal failure, and five patients experienced adverse events of grade 2 or less.

[0222] Example 8 - Evaluation of the Best Percent Change in Plasma PSA from Pre - treatment Levels in mCRPC Patients and Subsequent Evaluation of Biomarker Status after Oral Administration of Compound (I - g) Twenty patients were orally administered compound (I - g) at doses of 35 mg / day, 70 mg / day, 140 mg / day or 280 mg / day. The best percent change in plasma PSA from pre - treatment levels is provided in Figure 8 for each of the twenty patients. Patients 19 (second bar from the right) and 20 (right - most bar) showed at least a 50% decrease in PSA after treatment with compound (I - g).

[0223] The AR biomarker status of 12 patients who received oral administration of compound (I-g) at a dose of 140 mg / day or more was evaluated. Figure 9 shows the AR biomarker status of these 12 patients together with the best change rate of plasma PSA level. Patients with different AR biomarker status had different responses to the treatment with compound (I-g). In this study, for example, only patient 19 (the second bar from the right) and patient 20 (the rightmost bar) who both had AR mutations T878A and H875Y had at least a 50% decrease in PSA after treatment.

[0224] The main characteristics of patient 19 and patient 20 are summarized in Figure 10 and Figure 11A respectively. Figure 11B shows a CT scan of the tumor of patient 20 before treatment with compound (I-g). Figure 11C shows a CT scan of the tumor of patient 20 after 4 cycles, indicating a RECIST response.

[0225] Example 9 - Further Pharmacokinetic Data - Oral Administration of Compound (I-g) Compound (I-g) was orally administered at doses of 35 mg / day, 70 mg / day, 140 mg / day, and 280 mg / day. It was observed that treatment with compound (I-g) at doses of 140 mg / day and 280 mg / day entered the preclinical effective range related to tumor growth inhibition. (Figure 12) The average plasma concentration of compound (I-g) over a 24-hour period after administration on day 15 is provided in Figure 13 for all four doses tested (35 mg / day, 70 mg / day, 140 mg / day, and 280 mg / day).

[0226] Equivalents Those skilled in the art will recognize, or be able to ascertain by means of only a little routine experimentation, many equivalents to the specific embodiments specifically described herein. Such equivalents are intended to be encompassed by the following claims.

[0227] The methods of the present disclosure are described herein by reference to specific preferred embodiments. However, certain variations thereof will be apparent to those skilled in the art based on the disclosure described herein, and the present disclosure is not considered to be limited thereto.

[0228] 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 belongs. In this specification and the claims, the singular forms also include the plural forms unless the context clearly dictates otherwise.

[0229] Of course, at least a part of the description of the present disclosure is simplified so as to focus on elements related to a clear understanding of the present disclosure. However, for the sake of clarity, excluding other elements understood by those skilled in the art may constitute a part of the present disclosure. However, since such elements are well known in the art and do not necessarily contribute to a better understanding of the present disclosure, the description of such elements is not provided herein.

[0230] Furthermore, unless the method depends on a specific order of the steps specified herein, the specific order of the steps recited in the claims should not be construed as a limitation on that claim.

[0231] All patents, patent applications, references, and published documents cited herein are hereby incorporated by reference in their entirety as if fully set forth. Such documents are not admitted to be prior art to the present disclosure.

Claims

1. A pharmaceutical composition for treating prostate cancer in a subject in need of treatment for prostate cancer, comprising a therapeutically effective amount of a compound of formula (I-g): or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is from about 35 mg to about 1000 mg, and is administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

2. A pharmaceutical composition for treating prostate cancer in a subject in need of treatment for prostate cancer, comprising a therapeutically effective amount of a compound of formula (I-g): comprising, wherein the therapeutically effective amount of the compound of formula (I-g) is from about 35 mg to about 1000 mg, and is administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

3. The pharmaceutical composition according to claim 1 or 2, wherein the prostate cancer is castration-resistant prostate cancer.

4. The pharmaceutical composition according to claim 1 or 2, wherein the prostate cancer is metastatic prostate cancer.

5. The pharmaceutical composition according to claim 1 or 2, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is administered orally to the subject.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is administered to the subject once a day, twice a day, three times a day, or four times a day.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is administered to the subject once a day.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is administered to the subject once or in two, three, or four divided doses.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is from about 270 mg to about 300 mg.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is from about 390 mg to about 420 mg.

12. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is from about 400 mg to about 430 mg.

13. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 35 mg.

14. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 100 mg.

15. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 140 mg.

16. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 150 mg.

17. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 200 mg.

18. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 250 mg.

19. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 280 mg.

20. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 300 mg.

21. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 350 mg.

22. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 400 mg.

23. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is about 420 mg.

24. The therapeutically effective amount of the compound of formula (I-g), or a pharmaceutically acceptable salt thereof, results in a 15-day average AUC greater than about 4,500 ng*hr / mL, about 4,600 ng*hr / mL, about 4,700 ng*hr / mL, about 4,800 ng*hr / mL, about 4,900 ng*hr / mL, about 5,000 ng*hr / mL, about 5,100 ng*hr / mL, about 5,200 ng*hr / mL, about 5,300 ng*hr / mL, 5,400 ng*hr / mL, about 5,500 ng*hr / mL, about 5,600 ng*hr / mL, about 5,700 ng*hr / mL, about 5,800 ng*hr / mL, about 5,900 ng*hr / mL, or about 6,000 ng*hr / mL ０－２４ The pharmaceutical composition according to any one of claims 1 to 23, which brings about

25. The average AUC on day 15, where the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof is greater than about 4,500 ng*hr / mL and less than about 5,500 ng*hr / mL ０－２４ The pharmaceutical composition according to any one of claims 1 to 23, which provides this.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof provides an average C on day 15 that is greater than about 300 ng / mL and less than about 400 ng / mL. ｍａｘ ​

27. The pharmaceutical composition according to any one of claims 1 to 25, wherein the therapeutically effective amount of the compound of formula (I-g) or a pharmaceutically acceptable salt thereof results in a mean C on day 15 greater than about 330 ng / mL, about 335 ng / mL, about 340 ng / mL, about 345 ng / mL, about 350 ng / mL, about 355 ng / mL, about 360 ng / mL, about 365 ng / mL, about 370 ng / mL, about 375 ng / mL, or about 380 ng / mL ｍａｘ ​

28. The pharmaceutical composition according to any one of claims 1 to 27, formulated as a tablet.

29. The pharmaceutical composition according to claim 28, wherein the tablet comprises a compound of formula (I-g), or a pharmaceutically acceptable salt thereof, and optionally one or more of an emulsifier, a surfactant, a binder, a disintegrant, a lubricant, and a glidant.

30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the subject is in a fed state.

31. The pharmaceutical composition according to any one of claims 1 to 29, wherein the subject is in a fasting state.

32. A pharmaceutical composition for treating prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): or a pharmaceutically acceptable salt thereof, and being administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

33. A pharmaceutical composition for treating prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): comprising and being administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

34. A pharmaceutical composition for treating metastatic prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): or a pharmaceutically acceptable salt thereof, and being administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

35. A pharmaceutical composition for treating metastatic prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): comprising and being administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

36. A pharmaceutical composition for treating castration-resistant prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): or a pharmaceutically acceptable salt thereof, and being administered to the subject simultaneously, separately, or sequentially with an effective amount of abiraterone acetate.

37. A pharmaceutical composition for treating castration-resistant prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): comprising A pharmaceutical composition that is administered to the subject simultaneously with, separately from, or sequentially with an effective amount of abiraterone acetate.

38. A pharmaceutical composition for treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): or a pharmaceutically acceptable salt thereof, A pharmaceutical composition that is administered to the subject simultaneously with, separately from, or sequentially with an effective amount of abiraterone acetate.

39. A pharmaceutical composition for treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (I-g): comprising A pharmaceutical composition that is administered to the subject simultaneously with, separately from, or sequentially with an effective amount of abiraterone acetate.

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