Compounds and methods for targeted degradation of the androgen receptor

Abstract

The present disclosure relates to a method of treating prostate cancer, including prostate cancer comprising at least one somatic AR tumor mutation in a subject, e.g., metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive prostate cancer, NHA-naive metastatic prostate cancer, NHA-naive castration-resistant prostate cancer, NHA-naive castration-sensitive prostate cancer, NHA-naive metastatic castration-resistant prostate cancer, and NHA-naive metastatic castration-sensitive prostate cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. JPEG2026500894000245.jpg50170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application No. 63 / 418,926 filed October 24, 2022, U.S. Provisional Application No. 63 / 418,927 filed October 24, 2022, U.S. Provisional Application No. 63 / 434,813 filed December 22, 2022, U.S. Provisional Application No. 63 / 493,309 filed March 30, 2023, U.S. Provisional Application No. 63 / 496,008 filed April 13, 2023, U.S. Provisional Patent Application No. 63 / 506,829 filed June 7, 2023, U.S. Provisional Application No. 63 / 582,504 filed September 13, 2023, and U.S. Provisional Application No. 63 / 592,176 filed October 21, 2023. The contents of that provisional application are incorporated herein by reference in their entirety.

[0002] Incorporation by reference of sequence listing The contents of the electronic sequence listing file entitled "ARVN-016-001WO_ST26.xml", created on October 20, 2023, and having a size of 2,925 bytes, are incorporated herein by reference in their entirety.

[0003] The present disclosure provides methods of using bifunctional compounds to treat prostate cancer. [Background technology]

[0004] Most small molecule drugs bind to tight, specific pockets in enzymes or receptors. Protein-protein interactions, on the other hand, are notoriously difficult to target with small molecules due to their large contact surfaces and shallow grooves or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) are attractive therapeutic targets because they confer substrate specificity to ubiquitination. Developing ligands for E3 ligases has proven challenging, in part because they must inhibit protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases.

[0005] One E3 ubiquitin ligase with therapeutic potential is cereblon, a protein encoded by the CRBN gene in humans. Thalidomide and its analogs, such as pomalidomide and lenalidomide, are known to bind to cereblon. These drugs bind to cereblon, altering the specificity of the complex and inducing the ubiquitination and degradation of transcription factors essential for the growth of multiple myeloma. In fact, high cereblon expression is associated with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0006] The androgen receptor (AR) belongs to the nuclear hormone receptor family, which is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782-97; Vitam. Horn. 1999, 55:309-52). In the absence of androgens, the AR is bound by heat shock protein 90 (Hsp90) in the cytosol. When androgens bind to the AR, its conformational change releases the AR from Hsp90 and exposes a nuclear localization signal (NLS). The latter allows the AR to translocate to the nucleus, where it acts as a transcription factor and promotes the expression of genes involved in male sexual characteristics (Endocr. Rev. 1987, 8(1):1-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency causes androgen insensitivity syndrome, formerly known as testicular feminization syndrome.

[0007] AR is involved in the development of male sexual characteristics and is also a well-documented oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). A commonly measured target gene of AR activity is the secreted prostate-specific antigen (PSA) protein. Current treatment strategies for prostate cancer involve inhibiting the androgen-AR axis in two ways. The first approach relies on androgen reduction, while the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823-824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. An alternative approach for the treatment of prostate cancer involves eliminating the AR protein.

[0008] Because AR is a key driver of tumorigenesis in many forms of prostate cancer, its loss should lead to a beneficial response to treatment. There is a continuing need in the art for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy's disease.

[0009] However, non-specific effects and the inability to fully target and regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anti-cancer drugs. Thus, small molecule therapeutics that exploit or enhance the substrate specificity of cereblon while being "tunable" to target and specifically regulate a broad range of protein classes would be highly useful as therapeutics.

[0010] More than 70 different somatic missense AR tumor mutations have been identified in prostate cancer patients (Gottlieb, B., Hum. Mutat. 2004, 23:527-533). Most of these AR tumor mutations are located in the ligand-binding domain. Without being bound by theory, AR tumor mutations in the ligand-binding domain reduce ligand specificity, thereby allowing AR to function independently of androgen. Such AR tumor mutations provide tumor cells with the ability to grow in an androgen-deficient environment, and are therefore selected for prostate cancer treatments that block or reduce androgen levels (e.g., luteinizing hormone-releasing hormone agonists). Accordingly, AR tumor mutations are observed more frequently in patients with advanced androgen-independent tumors compared with patients with early-stage prostate cancer (Taplin, ME, et al. N. Engl. J. Med. (1995) 332:1393-1398, Marcelli, M., et al. Cancer Res. (2000) 60:944-949). Summary of the Invention

[0011] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0012] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] The prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0013] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0014] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0015] In some embodiments, the prostate cancer is prostate adenocarcinoma.

[0016] In some embodiments, the prostate cancer is metastatic prostate cancer.

[0017] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0018] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0019] In some embodiments, the prostate cancer is advanced metastatic castration-resistant prostate cancer.

[0020] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of compound A is about 5 mg to about 750 mg.

[0021] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of compound A is about 5 mg to about 750 mg.

[0022] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0023] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0024] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0025] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0026] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA) naive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0027] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA) naive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the therapeutically effective amount of compound A is about 5 mg to about 750 mg.

[0028] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0029] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0030] In some embodiments, the NHA-naive prostate cancer is NHA-naive metastatic prostate cancer.

[0031] In some embodiments, the NHA-naive prostate cancer is NHA-naive castration-resistant prostate cancer.

[0032] In some embodiments, the NHA-naive prostate cancer is NHA-naive castration-sensitive prostate cancer.

[0033] In some embodiments, the NHA-naive prostate cancer is NHA-naive metastatic castration-resistant prostate cancer.

[0034] In some embodiments, the NHA-naive prostate cancer is NHA-naive metastatic castration-sensitive prostate cancer.

[0035] In some embodiments, the NHA-naive prostate cancer has not been previously treated with a second-generation antiandrogen.

[0036] In some embodiments, the NHA-naive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0037] In some embodiments, the NHA-naive prostate cancer has not been previously treated with abiraterone acetate.

[0038] In some embodiments, the NHA-naive prostate cancer has not previously been treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0039] In some embodiments, the NHA-naive prostate cancer has not been previously treated with an anti-cancer drug.

[0040] In some embodiments, the subject has not previously been administered an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0041] In some embodiments, the subject has not previously been administered abiraterone acetate.

[0042] In some embodiments, the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0043] In some embodiments, the subject has not previously been administered an anti-cancer drug.

[0044] In some embodiments, the therapeutically effective amount of Compound A is administered orally to the subject.

[0045] In some embodiments, the therapeutically effective amount of Compound A is administered to the subject once daily, twice daily, three times daily, or four times daily.

[0046] In some embodiments, the therapeutically effective amount of Compound A is administered to the subject once daily.

[0047] In some embodiments, the therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0048] In some embodiments, the therapeutically effective amount of Compound A is from about 5 mg to about 250 mg.

[0049] In some embodiments, the therapeutically effective amount of Compound A is from about 250 mg to about 500 mg.

[0050] In some embodiments, the therapeutically effective amount of Compound A is from about 500 mg to about 750 mg.

[0051] In some embodiments, the therapeutically effective amount of Compound A is about 100 mg.

[0052] In some embodiments, the therapeutically effective amount of Compound A is about 150 mg.

[0053] In some embodiments, the therapeutically effective amount of Compound A is about 200 mg.

[0054] In some embodiments, the therapeutically effective amount of Compound A is about 300 mg.

[0055] In some embodiments, the therapeutically effective amount of Compound A is about 320 mg.

[0056] In some embodiments, the therapeutically effective amount of Compound A is about 400 mg.

[0057] In some embodiments, the therapeutically effective amount of Compound A is about 480 mg.

[0058] In some embodiments, the therapeutically effective amount of Compound A is about 500 mg.

[0059] In some embodiments, the subject is fed at the time of administration.

[0060] In some embodiments, the subject is fasted at the time of administration.

[0061] In some embodiments, the prostate cancer comprises at least one somatic AR tumor mutation.

[0062] In some embodiments, the prostate cancer subject comprises at least one somatic AR tumor mutation.

[0063] In some embodiments, the at least one somatic AR tumor mutation is a missense mutation in the AR ligand binding domain.

[0064] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, E898X, and any combination thereof, wherein "X" is alanine (A), valine (V), leucine (L), isoleucine (I), or methyl. (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E), other than the wild-type residue at that position.

[0065] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, E898G, and any combination thereof.

[0066] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof.

[0067] In some embodiments, the at least one somatic AR tumor mutation is: (i) L702H, (ii) T878A, (iii) T878S, (iv) H875Y, (v) L702H and T878A, (vi) L702H and T878S, (vii) L702H and H875Y, (viii) T878A and H875Y, (ix) T878S and H875Y, (x) L702H, T878A, and H875Y, or (xi) L702H, T878S, and H875Y.

[0068] In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0069] In some embodiments, the therapeutically effective amount of abiraterone acetate is from about 250 mg to about 1500 mg.

[0070] In some embodiments, the therapeutically effective amount of abiraterone acetate is about 1000 mg.

[0071] In some embodiments, the therapeutically effective amount of abiraterone acetate is administered orally to the subject.

[0072] In some embodiments, the therapeutically effective amount of abiraterone acetate is administered to the subject once daily.

[0073] In some embodiments, the methods of the present application further comprise administering a corticosteroid to said subject.

[0074] 60. The method of claim 59, wherein, in some embodiments, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of the corticosteroid is administered to the subject.

[0075] In some embodiments, the corticosteroid is administered orally to the subject once daily.

[0076] In some embodiments, the corticosteroid is administered orally to the subject twice daily.

[0077] In some embodiments, the corticosteroid is prednisone, prednisolone, methylprednisolone, cortisone, cortisol, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

[0078] In some embodiments, the corticosteroid is prednisone.

[0079] In some embodiments, the corticosteroid is prednisolone.

[0080] In some embodiments, the methods of the present application include the subject discontinuing use of a PPI before initiating administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the PPI is esomeprazole.

[0082] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the prostate cancer having at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0083] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the prostate cancer having at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0084] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer having at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0085] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer having at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or advanced metastatic castration-resistant prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0086] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is prostate adenocarcinoma.

[0087] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is metastatic prostate cancer.

[0088] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is castration-resistant prostate cancer.

[0089] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is metastatic castration-resistant prostate cancer.

[0090] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is advanced metastatic castration-resistant prostate cancer.

[0091] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0092] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0093] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0094] In one aspect, the present application relates to a method of treating prostate cancer harboring at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer, and the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0095] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is castration-sensitive prostate cancer.

[0096] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation is metastatic castration-sensitive prostate cancer.

[0097] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0098] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the therapeutically effective amount of compound A is about 5 mg to about 750 mg.

[0099] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer having at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0100] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer having at least one somatic AR tumor mutation in a subject, the method comprising administering to a subject in need thereof: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate, wherein the therapeutically effective amount of Compound A is about 5 mg to about 750 mg.

[0101] In some embodiments, the NHA-naive prostate cancer with at least one somatic AR tumor mutation is NHA-naive metastatic prostate cancer.

[0102] In some embodiments, the NHA-naive prostate cancer with at least one somatic AR tumor mutation is NHA-naive castration-resistant prostate cancer.

[0103] In some embodiments, the NHA-naive prostate cancer with at least one somatic AR tumor mutation is NHA-naive castration-sensitive prostate cancer.

[0104] In some embodiments, the NHA-naive prostate cancer with at least one somatic AR tumor mutation is NHA-naive metastatic castration-resistant prostate cancer.

[0105] In some embodiments, the NHA-naive prostate cancer with at least one somatic AR tumor mutation is NHA-naive metastatic castration-sensitive prostate cancer.

[0106] In some embodiments, the at least one somatic AR tumor mutation is a missense mutation in the AR ligand binding domain.

[0107] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, E898X, and any combination thereof, wherein "X" is alanine (A), valine (V), leucine (L), isoleucine (I), or methyl. (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E), other than the wild-type residue at that position.

[0108] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, E898G, and any combination thereof.

[0109] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof.

[0110] In some embodiments, the at least one somatic AR tumor mutation is selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof.

[0111] In some embodiments, the at least one somatic AR tumor mutation is: (i) L702H, (ii) T878A, (iii) T878S, (iv) H875Y, (v) L702H and T878A, (vi) L702H and T878S, (vii) L702H and H875Y, (viii) T878A and H875Y, (ix) T878S and H875Y, (x) L702H, T878A, and H875Y, or (xi) L702H, T878S, and H875Y.

[0112] In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0113] In one aspect, the present application provides a method for producing a medicament for a method of manufacturing a medicament for a medical device, comprising: (a) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (b) A combined preparation of abiraterone acetate for simultaneous, separate or sequential use in a method for treating prostate cancer in a subject, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0114] In some embodiments, the method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) A once-daily oral dose of about 250 mg to about 1500 mg of abiraterone acetate.

[0115] In some embodiments, the method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) A once-daily oral dose of approximately 1000 mg of abiraterone acetate.

[0116] In one aspect, the present application provides a method for producing a medicament for a method of manufacturing a medicament for a medical device, comprising: (a) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (b) A combination preparation of abiraterone acetate for simultaneous, separate or sequential use in the treatment of novel hormonal agent (NHA)-naive prostate cancer in a subject.

[0117] In some embodiments, the method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) A once-daily oral dose of about 250 mg to about 1500 mg of abiraterone acetate.

[0118] In some embodiments, the method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) A once-daily oral dose of approximately 1000 mg of abiraterone acetate.

[0119] In some embodiments, the novel hormonal agent (NHA)-naive prostate cancer is NHA-naive metastatic prostate cancer, NHA-naive castration-resistant prostate cancer, NHA-naive castration-sensitive prostate cancer, NHA-naive metastatic castration-resistant prostate cancer, or NHA-naive metastatic castration-sensitive prostate cancer.

[0120] In one aspect, the present application provides a method for producing a medicament for a method of manufacturing a medicament for a medical device, comprising: Compound A for use in a method for treating prostate cancer in a subject; [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) A once-daily oral administration of about 250 mg to about 1500 mg of abiraterone acetate, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0121] In one aspect, the present application provides a method for producing a medicament for a method of manufacturing a medicament for a medical device, comprising: Compound A for use in a method for treating prostate cancer in a subject; [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) about 1000 mg of abiraterone acetate administered orally once daily, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0122] In one aspect, the present application provides Compound A for use in a method for treating novel hormonal agent (NHA)-naive prostate cancer in a subject, [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) A once-daily oral dose of about 250 mg to about 1500 mg of abiraterone acetate.

[0123] In one aspect, the present application provides Compound A for use in a method for treating novel hormonal agent (NHA)-naive prostate cancer in a subject, [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) A once-daily oral dose of approximately 1000 mg of abiraterone acetate.

[0124] In some embodiments, the novel hormonal agent (NHA)-naive prostate cancer is NHA-naive metastatic prostate cancer, NHA-naive castration-resistant prostate cancer, NHA-naive castration-sensitive prostate cancer, NHA-naive metastatic castration-resistant prostate cancer, or NHA-naive metastatic castration-sensitive prostate cancer.

[0125] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof.

[0126] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] The method comprises administering a therapeutically effective amount of

[0127] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0128] In one aspect, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject is in a fed state at the time of administration.

[0129] In one aspect, the application relates to a method of treating prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof.

[0130] In one aspect, the application relates to a method of treating prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0131] In one aspect, the application relates to a method of treating prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer, the method comprising administering to a subject in need thereof Compound A, [ka] The method comprises administering a therapeutically effective amount of

[0132] In one aspect, the application relates to a method of treating prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject is in a fed state at the time of administration.

[0133] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof.

[0134] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0135] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] The method comprises administering a therapeutically effective amount of

[0136] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject is in a fed state at the time of administration.

[0137] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject with prostate cancer comprises at least one somatic AR tumor mutation.

[0138] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration, and the prostate cancer subject comprises at least one somatic AR tumor mutation.

[0139] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject with prostate cancer comprises at least one somatic AR tumor mutation.

[0140] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer, novel hormonal agent (NHA)-naive metastatic prostate cancer, novel hormonal agent (NHA)-naive castration-resistant prostate cancer, novel hormonal agent (NHA)-naive castration-sensitive prostate cancer, novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer, or novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject is in a fed state at the time of administration, and the prostate cancer subject comprises at least one somatic AR tumor mutation.

[0141] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0142] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0143] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0144] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0145] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with prostate adenocarcinoma contains at least one somatic AR tumor mutation.

[0146] In one aspect, the present application relates to a method of treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with prostate adenocarcinoma contains at least one somatic AR tumor mutation.

[0147] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0148] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0149] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0150] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0151] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The metastatic prostate cancer subject contains at least one somatic AR tumor mutation.

[0152] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The metastatic prostate cancer subject contains at least one somatic AR tumor mutation.

[0153] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0154] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0155] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0156] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0157] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The castration-resistant prostate cancer subject comprises at least one somatic AR tumor mutation.

[0158] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The castration-resistant prostate cancer subject comprises at least one somatic AR tumor mutation.

[0159] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0160] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0161] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0162] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0163] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-resistant prostate cancer contains at least one somatic AR tumor mutation.

[0164] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-resistant prostate cancer contains at least one somatic AR tumor mutation.

[0165] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0166] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0167] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0168] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0169] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with advanced metastatic castration-resistant prostate cancer contains at least one somatic AR tumor mutation.

[0170] In one aspect, the present application relates to a method of treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with advanced metastatic castration-resistant prostate cancer contains at least one somatic AR tumor mutation.

[0171] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0172] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0173] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0174] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising: (i) Compound A, [ka] a therapeutically effective amount of (ii) comprising a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0175] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The castration-sensitive prostate cancer subject contains at least one somatic AR tumor mutation.

[0176] In one aspect, the present application relates to a method of treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The castration-sensitive prostate cancer subject contains at least one somatic AR tumor mutation.

[0177] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0178] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0179] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0180] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject has not previously been administered a novel hormone agent (NHA). In some embodiments, the NHA is a second-generation antiandrogen. In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0181] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-sensitive prostate cancer contains at least one somatic AR tumor mutation.

[0182] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-sensitive prostate cancer contains at least one somatic AR tumor mutation.

[0183] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0184] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0185] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive prostate cancer subjects contain at least one somatic AR tumor mutation.

[0186] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive prostate cancer subjects contain at least one somatic AR tumor mutation.

[0187] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0188] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0189] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive metastatic prostate cancer subjects contain at least one somatic AR tumor mutation.

[0190] In one aspect, the present application relates to a method of treating metastatic prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive metastatic prostate cancer subjects contain at least one somatic AR tumor mutation.

[0191] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0192] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0193] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive castration-resistant prostate cancer subjects contain at least one somatic AR tumor mutation.

[0194] In one aspect, the present application relates to a method of treating castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive castration-resistant prostate cancer subjects contain at least one somatic AR tumor mutation.

[0195] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0196] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0197] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive castration-sensitive prostate cancer subjects contain at least one somatic AR tumor mutation.

[0198] In one aspect, the present application relates to a method of treating novel hormonal agent (NHA)-naive castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The novel hormonal agent (NHA)-naive castration-sensitive prostate cancer subjects contain at least one somatic AR tumor mutation.

[0199] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0200] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0201] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-resistant prostate cancer who is naive to the novel hormonal agent (NHA) contains at least one somatic AR tumor mutation.

[0202] In one aspect, the present application relates to a method of treating metastatic castration-resistant prostate cancer in a subject who is naive to a novel hormonal agent (NHA), the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-resistant prostate cancer who is naive to the novel hormonal agent (NHA) contains at least one somatic AR tumor mutation.

[0203] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA) in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate.

[0204] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA) in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate.

[0205] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA) in a subject, the method comprising administering to the subject: (i) Compound A, [ka] or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-sensitive prostate cancer who is naive to the novel hormonal agent (NHA) contains at least one somatic AR tumor mutation.

[0206] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA) in a subject, the method comprising administering to the subject: (i) Compound A, [ka] a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The subject with metastatic castration-sensitive prostate cancer who is naive to the novel hormonal agent (NHA) contains at least one somatic AR tumor mutation.

[0207] In one aspect, the present application relates to a method of treating prostate cancer that is not novel hormonal agent (NHA) naive in a subject, optionally wherein the subject's prostate cancer has previously been treated with one, two, or more NHAs, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof.

[0208] In one aspect, the present application relates to a method of treating prostate cancer that is not novel hormonal agent (NHA) naive in a subject, optionally wherein the subject's prostate cancer has previously been treated with one, two, or more NHAs, the method comprising administering to a subject in need thereof Compound A, [ka] or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0209] In one aspect, the present application relates to a method of treating prostate cancer that is not novel hormonal agent (NHA) naive in a subject, optionally wherein the subject's prostate cancer has previously been treated with one, two, or more NHAs, the method comprising administering to a subject in need thereof Compound A, [ka] The method comprises administering a therapeutically effective amount of

[0210] In one aspect, the present application relates to a method of treating prostate cancer that is not novel hormonal agent (NHA) naive in a subject, optionally wherein the subject's prostate cancer has previously been treated with one, two, or more NHAs, the method comprising administering to a subject in need thereof Compound A, [ka] wherein the subject is in a fed state at the time of administration.

[0211] In some embodiments, the therapeutically effective amount of Compound A is administered orally to the subject.

[0212] In some embodiments, the therapeutically effective amount of Compound A is administered to the subject once daily, twice daily, three times daily, or four times daily.

[0213] In some embodiments, the therapeutically effective amount of Compound A is administered to the subject once daily.

[0214] In some embodiments, the therapeutically effective amount of Compound A is administered to the subject all at once or in two, three, or four divided doses.

[0215] In some embodiments, the therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

[0216] In some embodiments, the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0217] In some embodiments, the therapeutically effective amount of Compound A is from about 10 mg to about 500 mg.

[0218] In some embodiments, the therapeutically effective amount of Compound A is from about 20 mg to about 250 mg.

[0219] In some embodiments, the therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0220] In some embodiments, the therapeutically effective amount of Compound A is about 100 mg.

[0221] In some embodiments, the therapeutically effective amount of Compound A is 100 mg.

[0222] In some embodiments, the therapeutically effective amount of Compound A is about 150 mg.

[0223] In some embodiments, the therapeutically effective amount of Compound A is 150 mg.

[0224] In some embodiments, the therapeutically effective amount of Compound A is about 200 mg.

[0225] In some embodiments, the therapeutically effective amount of Compound A is 200 mg.

[0226] In some embodiments, the therapeutically effective amount of Compound A is about 300 mg.

[0227] In some embodiments, the therapeutically effective amount of Compound A is 300 mg.

[0228] In some embodiments, the therapeutically effective amount of Compound A is about 320 mg.

[0229] In some embodiments, the therapeutically effective amount of Compound A is 320 mg.

[0230] In some embodiments, the therapeutically effective amount of Compound A is about 400 mg.

[0231] In some embodiments, the therapeutically effective amount of Compound A is 400 mg.

[0232] In some embodiments, the therapeutically effective amount of Compound A is about 480 mg.

[0233] In some embodiments, the therapeutically effective amount of Compound A is 480 mg.

[0234] In some embodiments, the therapeutically effective amount of Compound A is about 500 mg.

[0235] In some embodiments, the therapeutically effective amount of Compound A is 500 mg.

[0236] In some embodiments, the subject is fed at the time of administration.

[0237] In some embodiments, the subject is fasted at the time of administration.

[0238] In some embodiments, the methods of the present application further comprise administering a PPI or an H2 compound to the subject. In some embodiments, the methods of the present application further comprise administering a PPI or an H2 compound to the subject before initiating administration of Compound A.

[0239] In some embodiments, the methods of the present application further comprise discontinuing administration of the PPI or H2 compound to the subject before initiating administration of Compound A. In some embodiments, administration of the PPI or H2 compound is discontinued in the subject at a time point before initiating administration of Compound A, which time point is at least 10 hours. In some embodiments, the methods of the present application further comprise reducing administration of the PPI or H2 compound to the subject before initiating administration of a therapeutically effective amount of Compound A. In some embodiments, administration of the PPI or H2 compound is reduced to a time point before initiating administration of Compound A in the subject, which time point is at least 10 hours.

[0240] In some embodiments, the PPI or H2 compound is esomeprazole.

[0241] In some embodiments, the method further comprises administering to a subject in need thereof an effective amount of at least one additional anti-cancer agent.

[0242] In some embodiments, the additional anticancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, or zoledronic acid.

[0243] In some embodiments, the prostate cancer comprises at least one somatic AR tumor mutation.

[0244] In some embodiments, the prostate cancer subject comprises at least one somatic AR tumor mutation.

[0245] In some embodiments, the at least one somatic AR tumor mutation is: (i) selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof; (ii) L702H, (iii) T878A, (iv) T878S, (v) H875Y, (vi) L702H and T878A, (vii) L702H and T878S, (viii) L702H and H875Y, (ix) T878A and H875Y, (x) T878S and H875Y, (xi) L702H, T878A, and H875Y, or (xii) L702H, T878S, and H875Y.

[0246] In one aspect, the present application relates to a method of treating prostate cancer in a subpopulation of subjects with prostate cancer, the method comprising: a. selecting a prostate cancer subject for treatment based on the subject's somatic AR tumor biomarker status; and b.Compound A, [ka] or a pharmaceutically acceptable salt thereof.

[0247] In one aspect, the present application relates to a method of treating prostate cancer in a subpopulation of subjects with prostate cancer, the method comprising: a. selecting a prostate cancer subject for treatment based on the subject's somatic AR tumor biomarker status; and b.Compound A, [ka] The method comprises administering a therapeutically effective amount of

[0248] In some embodiments, the subject's somatic AR tumor biomarker status comprises at least one somatic AR tumor mutation.

[0249] In some embodiments, the at least one somatic AR tumor mutation is: (i) selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof; (ii) L702H, (iii) T878A, (iv) T878S, (v) H875Y, (vi) L702H and T878A, (vii) L702H and T878S, (viii) L702H and H875Y, (ix) T878A and H875Y, (x) T878S and H875Y, (xi) L702H, T878A, and H875Y, or (xii) L702H, T878S, and H875Y.

[0250] In some embodiments, the subject's AR biomarker status is determined by ctDNA analysis, fluorescent in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

[0251] In some embodiments, the subject's AR biomarker status is determined in a blood sample obtained from the subject.

[0252] In some embodiments, the subject's AR biomarker status is determined in a solid biopsy obtained from the subject's tumor.

[0253] In some embodiments, the subject is also undergoing ongoing androgen deprivation therapy (ADT).

[0254] In some embodiments, the ADT comprises administration of a gonadotropin-releasing hormone analog or inhibitor to the subject.

[0255] In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is leuprolide, goserelin, triptorelin, histrelin, or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the subject has undergone an orchiectomy.

[0257] In some embodiments, the subject has been diagnosed with histologically, pathologically, or cytologically confirmed prostate adenocarcinoma.

[0258] In some embodiments, the subject has experienced prostate cancer progression after receiving at least one previously approved systemic therapy for metastatic prostate cancer prior to administration of a therapeutically effective amount of Compound A.

[0259] In some embodiments, the subject has experienced prostate cancer progression after receiving at least two previously approved systemic therapies for metastatic prostate cancer prior to administration of a therapeutically effective amount of Compound A.

[0260] In some embodiments, the previously approved systemic therapy for metastatic prostate cancer is a second-generation androgen inhibitor.

[0261] In some embodiments, the second-generation androgen inhibitor is abiraterone, abiraterone acetate, enzalutamide, darolutamide, apalutamide, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the subject has an ECOG performance status of 0 or 1.

[0263] In some embodiments, the subject does not have symptomatic brain metastases requiring greater than physiological replacement doses of steroids.

[0264] In some embodiments, the subject does not have active inflammatory bowel disease.

[0265] In some embodiments, the subject does not have chronic diarrhea.

[0266] In some embodiments, the subject does not have diverticular disease.

[0267] In some embodiments, the subject has not previously undergone gastrectomy.

[0268] In some embodiments, the subject has not previously undergone lap-band surgery.

[0269] In some embodiments, the subject has not received prior radiation therapy within 4 weeks prior to the first administration of a therapeutically effective amount of Compound A.

[0270] In some embodiments, the subject has not previously undergone radiation therapy that irradiates more than about 25% of the subject's bone marrow.

[0271] In some embodiments, the subject has not received an investigational drug within four weeks prior to the first administration of a therapeutically effective amount of Compound A.

[0272] In some embodiments, the subject has metastatic castration-resistant prostate cancer, and the subject's metastatic castration-resistant prostate cancer exhibits radiographic evidence of metastatic disease.

[0273] In some embodiments, the subject has metastatic castration-sensitive prostate cancer, and the subject's metastatic castration-sensitive prostate cancer exhibits radiographic evidence of metastatic disease.

[0274] In some embodiments, the prostate cancer is prostate adenocarcinoma.

[0275] In some embodiments, the prostate cancer is metastatic prostate cancer.

[0276] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0277] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0278] In some embodiments, the metastatic castration-resistant prostate cancer exhibits radiographic evidence of metastatic disease.

[0279] In some embodiments, the prostate cancer is advanced metastatic castration-resistant prostate cancer.

[0280] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0281] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0282] In some embodiments, the metastatic castration-sensitive prostate cancer exhibits radiographic evidence of metastatic disease.

[0283] In some embodiments, the prostate cancer is novel hormonal agent (NHA) naive prostate cancer.

[0284] In some embodiments, the prostate cancer is novel hormonal agent (NHA) naive metastatic prostate cancer.

[0285] In some embodiments, the prostate cancer is castration-resistant prostate cancer that is naive to novel hormonal agents (NHA).

[0286] In some embodiments, the prostate cancer is castration-sensitive prostate cancer that is naive to novel hormonal agents (NHA).

[0287] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0288] In some embodiments, the prostate cancer is advanced metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0289] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs).

[0290] In some embodiments, the prostate cancer has not been previously treated with a second-generation antiandrogen. In some embodiments, the prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0291] In some embodiments, the subject has not previously been administered a second-generation antiandrogen. In some embodiments, the subject has not previously been administered an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the subject has not previously been administered an androgen biosynthesis inhibitor. In some embodiments, the subject has not previously been administered an androgen receptor blocker. In some embodiments, the subject has not previously been administered abiraterone acetate. In some embodiments, the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0292] In some embodiments, the prostate cancer is novel hormonally naive (NHA) metastatic prostate cancer. In some embodiments, the novel hormonally naive (NHA) metastatic prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the novel hormonally naive (NHA) metastatic prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the novel hormonally naive (NHA) metastatic prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the novel hormonally naive (NHA) metastatic prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the novel hormonally naive (NHA) metastatic prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormonal agent (NHA)-naive metastatic prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0293] In some embodiments, the prostate cancer is hormonally naive (NHA)-naive castration-resistant prostate cancer. In some embodiments, the hormonally naive (NHA)-naive castration-resistant prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the hormonally naive (NHA)-naive castration-resistant prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the hormonally naive (NHA)-naive castration-resistant prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the hormonally naive (NHA)-naive castration-resistant prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the hormonally naive (NHA)-naive castration-resistant prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormonal agent (NHA)-naive castration-resistant prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0294] In some embodiments, the prostate cancer is hormonally naive (NHA)-naive castration-sensitive prostate cancer. In some embodiments, the hormonally naive (NHA)-naive castration-sensitive prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the hormonally naive (NHA)-naive castration-sensitive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the hormonally naive (NHA)-naive castration-sensitive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the hormonally naive (NHA)-naive castration-sensitive prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the hormonally naive (NHA)-naive castration-sensitive prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormonal agent (NHA)-naive castration-sensitive prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0295] In some embodiments, the prostate cancer is novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer. In some embodiments, the novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the novel hormonally (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-resistant prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0296] In some embodiments, the prostate cancer is novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0297] In some embodiments, the second-generation antiandrogen is an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0298] In some embodiments, the androgen biosynthesis inhibitor is abiraterone acetate.

[0299] In some embodiments, the androgen receptor blocker is selected from enzalutamide, darolutamide, and apalutamide.

[0300] In some embodiments, the prostate cancer is not novel hormonal agent (NHA) naive prostate cancer, and optionally the subject's prostate cancer has been previously treated with one, two, or more NHAs.

[0301] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings illustrating exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0302] [Figure 1] Figures A and B illustrate the general principle of function of proteolysis-inducing chimeric compounds. Figure A shows an exemplary proteolysis-inducing chimeric compound containing a protein targeting moiety (PTM, dark-shaded rectangle), a cereblon ubiquitin ligase-binding moiety (CLM, open triangle), and a linker moiety (black line) that connects or tethers the PTM to the CLM. Figure B illustrates the functional use of the proteolysis-inducing chimeric compounds described herein. Briefly, the CLM recognizes and binds to cereblon, an E3 ubiquitin ligase, and the PTM binds to an intracellular target protein, recruiting it to the cereblon E3 ubiquitin ligase. Typically, cereblon E3 ubiquitin ligase forms a complex with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (black circle) via an isopeptide bond to lysines on the target protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 2] Analysis of Compound A in an in vitro AR degradation assay performed on VCaP and LNCaP cancer cells harboring AR amplification and AR mutation (T878A), respectively. [Figure 3] 1 is a graph showing the ability of Compound A to degrade clinically relevant mutant AR. [Figure 4] Analysis of Compound A in an in vitro cereblon neomorphic substrate degradation assay performed in Ramos and SK-N-DZ cells. [Figure 5] 1 is a graph showing the effects of Compound A and Enzalutamide in an in vivo VCaP tumor xenograft study in intact mice. [Figure 6] 1 shows the effect of Compound A and Enzalutamide on plasma PSA levels in samples from an intact VCaP tumor model. [Figure 7] Figure 1 shows the best PSA50 % change from baseline in patients with AR ligand binding domain (LBD) mutations, including PSA50 response rates in patients with concomitant AR H875 / T878 / L702H mutations. [Figure 8A] This figure shows that Compound A inhibits PSA synthesis, blocks prostate cancer growth, and induces apoptosis in vertebrate-prostate cancer (VcaP) cells. The results of an experiment in which VCaP cells cultured in charcoal-stripped fetal bovine serum (CSS) supplemented with 0.1 nM R1881 (synthetic androgen) were treated with the indicated concentrations of Compound A or enzalutamide for 48 hours were shown. Intracellular prostate-specific antigen (PSA) levels were determined using a PSA enzyme-linked immunosorbent assay (ELISA). [Figure 8B] This figure shows that Compound A inhibits PSA synthesis, blocks prostate cancer growth, and induces apoptosis in vertebrate-prostate cancer (VcaP) cells. VCaP cells were cultured in a medium containing CSS and supplemented with 0.1 nM R1881, and treated with the indicated concentrations of Compound A or enzalutamide for 96 hours. Cell proliferation was determined using the CellTiter-Glo® assay. [Figure 8C] This figure shows that Compound A inhibits PSA synthesis, blocks prostate cancer growth, and induces apoptosis in vertebrate-prostate cancer (VcaP) cells. VCaP cells were cultured in a medium containing CSS and supplemented with 0.1 nM R1881, and treated with the indicated concentrations of Compound A for 72 hours. A Caspase-Glo® assay was performed to measure the level of apoptosis in the cells. [Figure 9]To evaluate whether Compound A can overcome the effects of residual androgens, we performed a cell proliferation assay in vitro under high-androgen conditions. VCaP cells were grown in CSS-containing medium in the presence of a fixed concentration of Compound A (300 nM) or enzalutamide (1,000 nM), and in the presence of increasing concentrations of the synthetic androgen R1881. R1881 alone promoted VCaP cell proliferation, demonstrating that proliferation can be induced by activation of the AR signaling pathway. VCaP cells were cultured for 5 days in medium containing CSS, the indicated concentrations of R1881, and either Compound A (300 nM) or enzalutamide (1,000 nM). Cell proliferation was determined using the CellTiter Glo® assay. [Figure 10] Figure 1 shows the degradation of AR proteins with clinically relevant point mutations M896V, T878A, F877L, L702H, and H875Y. HEK293 cells were stably transfected with plasmids expressing AR WT or the indicated AR mutants. Each cell line was treated with the indicated concentrations of Compound A for 24 hours. AR levels were determined by AR ELISA without background subtraction. HEK293 cells were stably transfected with plasmids expressing AR wild-type (WT) or the indicated AR mutants. Each cell line was treated with the indicated concentrations of Compound A for 24 hours. AR levels were determined by AR ELISA without background subtraction. [Figure 11] Figure 1 shows AR degradation in castrated CB17 / SCID male mice bearing VCaP xenografts treated with various single doses of Compound A (10, 3, 1, 0.3, 0.1, and 0.03 mg / kg). Tumors were harvested 16 hours after administration, and tumor AR levels were determined by Western blotting. A human mitochondrial-specific antibody (Mito.C) recognizing the antibody was used as a loading control. Quantification of AR levels obtained from Western blot is shown (lower panel). [Figure 12]Figure 1 shows tumor growth inhibition in castrated CB17 / SCID male mice bearing VCaP xenografts treated with Compound A (3, 1, 0.3, or 0.1 mg / kg) or enzalutamide (20 mg / kg). Enza = enzalutamide, PO = oral, QD = once daily, scid = severe combined immunodeficiency. Treatment groups (n = 10 per group) were compared by one-way analysis of variance (ANOVA). Note: ns = not significant, * = p < 0.05, ** = p ≤ 0.01, *** = p ≤ 0.001. [Figure 13] Figure 1 shows the results of a 10-day prostate regression study in adult rats. Enzalutamide and Compound A were administered orally once daily at the indicated doses. After 10 days of treatment, prostate tissue from each rat was isolated and weighed. Treatment groups (n = 5 per group) were compared by one-way ANOVA. Note: ns: not significant, *: p < 0.05, **: p ≤ 0.01. [Figure 14] Graph showing rapid decline in prostate-specific antigen (PSA) in metastatic castration-resistant prostate cancer (mCRPC) patients with wild-type AR. These results support development in the pre-nhA (pre-NHA) setting, including metastatic castration-sensitive prostate cancer (mCSPC). The evaluable analysis population includes all Compound A-treated participants with a baseline PSA assessment and a post-baseline PSA assessment since at least C1D28. PSA90, PSA50, and PSA30 responses are defined as a 90%, 50%, or 30% decline from baseline PSA, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0303] Sequence Listing All references to amino acid mutations in the androgen receptor are numbered relative to SEQ ID NO: 1, provided below: [ka]

[0304] definition All references to amino acid mutations in the androgen receptor are numbered relative to SEQ ID NO: 1 provided herein.

[0305] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin-conjugating enzyme, induces the attachment of ubiquitin to lysines on the target protein, subsequently targeting the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin-conjugating enzyme, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, resulting in a second ubiquitin being attached to the first, a third to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is attached to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but instead their cellular location or function may be altered, for example, through conjugation to other proteins that contain domains capable of binding to ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to generate polyubiquitin, which is recognized by the proteasome.

[0306] As used herein, "compound," "bifunctional compound," or "compound of the disclosure," as used herein, refers to the compounds disclosed by structure in the Tables and Examples below.

[0307] The terms "substituted" or "optionally substituted" are intended to mean, independently (i.e., when multiple substituents occur, each substituent is independent of another substituent) one or more substituents (which moieties in the compounds of the present disclosure may independently include up to five substituents, preferably up to three substituents, often one or two substituents, and which may themselves be further substituted), on a carbon (or nitrogen) anywhere on the molecule, as the case may be, and include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably one, two, or three halogens, particularly alkyl, especially methyl groups, e.g., trifluoromethyl), alkyl groups (preferably C1-C2), and the like). 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, for example, benzyl or benzoyl), alkoxy groups (e.g., C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), alkylene ester (the attachment is on the alkylene group rather than the ester functionality, which is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including 5- or 6-membered cyclic alkylene amines). and further including a C1-C6 alkylamine or a C1-C6 dialkylamine, where the alkyl group is optionally substituted with one or two hydroxyl groups) or an optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) group (which may optionally be substituted with a polyethylene glycol chain to which is further attached an alkyl group containing a single halogen, preferably chlorine, substituent), hydrazine, an amide preferably substituted with one or two C1-C6 alkyl groups (including a carboxamide optionally substituted with one or two C1-C6 alkyl groups), an alkanol (preferably C1-C6 alkyl or aryl), or an alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, where R1 and R2 are each as specifically described herein and R3 is H or a C1-C6 alkyl group, and in this regard, preferably R1, R2, and R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly linked to the substituted moiety, or alternatively, the substituent may be optionally substituted on the substituted moiety (preferably, in the case of an aryl or heteroaryl moiety) with -(CH2). m - or alternatively optionally substituted -(OCH2) m -, -(OCH2CH2) m - or -(CH2CH2O) mThe alkylene group -(CH2) may be linked via a - group, which may be substituted with any one or more of the above substituents. m -or-(CH2) n -groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere along the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chains of amino acids specifically described herein, and optionally substituted amide (preferably carboxamido substituted as described above) or urethane groups (often containing one or two C0-C6 alkyl substituents, which group(s) may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids specifically described herein. In the present disclosure, moieties contained in molecules may be optionally substituted with up to 5 substituents, preferably up to 3. In most cases, moieties in the present disclosure that are substituted will be substituted with 1 or 2 substituents.

[0308] The term "substituted" (each substituent is independent of any other substituent) also refers, depending on the context of its use, to C-C alkyl, C-C alkoxy, halogen, amide, carboxamide, sulfone, including sulfonamide, keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C-C alkylene-NR1R2, mono- or di-C-C alkyl-substituted amines, which may optionally be substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms, depending on the context, unless otherwise indicated. In certain embodiments, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, and -(CH2) m - (where m and n are 1, 2, 3, 4, 5 or 6 as appropriate), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R Sis C1-C6 alkyl or -(CH2) m Examples of the substituent include -NR1R2 groups), NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of use of the substituent. R1 and R2 are each, depending on the context, H or a C1-C6 alkyl group (which may optionally be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" also refers to an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as specifically described herein, depending on the chemical context of the defined compound and the substituents used. Alkylene groups may also be substituted with the substituents specifically disclosed herein, preferably an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), the side chain of an amino acid group as specifically described herein, an amide group as described herein above, or a urethane group O-C(O)-NR1R2 group, where R1 and R2 are as specifically described herein, although many other groups can also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer substituents, preferably one or two substituents. In compounds where substitution is required at a particular position in the molecule (primarily for valence reasons) but no substitution is indicated, that substituent is interpreted or understood to be H unless the circumstances of the substitution suggest otherwise.

[0309] The terms "aryl" or "aromatic" refer to substituted (as specifically described herein) or unsubstituted monovalent aromatic radicals having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), as the case may be, and may be attached to the compounds of the present disclosure at any available stable position on the ring(s) or as specifically shown in the existing chemical structure. Other examples of aryl groups, as the case may be, may include heterocyclic aromatic ring systems, i.e., "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, among others, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be optionally substituted as described above.Among the heteroaryl groups that may be mentioned are especially nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidine aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0310] The term "substituted aryl" refers to an aromatic carbocyclic group composed of at least one aromatic ring or composed of multiple fused rings in which at least one ring is aromatic, and the ring(s) are substituted with one or more substituents. For example, an aryl group can include a substituent(s) selected from the following: -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n-C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amines, mono- or di(C1-C6 alkyl)amines, where the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups; OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups, each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position; optionally substituted phenyl groups, where the phenyl group is , which itself is preferably substituted with a linker group attached to an ABM group, including a ULM group), and / or at least one of F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN group (at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, an optionally substituted oxazole, including methyl-substituted oxazole. optionally substituted thiazoles including methyl-substituted thiazoles, optionally substituted isothiazoles including methyl-substituted isothiazoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl-substituted pyridine groups or oxapyridine groups (where the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines, and combinations thereof.

[0311] The term "heteroaryl" or "hetaryl" refers to an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted benzimidazole, a benzodiazole, a benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and / or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably methyl and / or thiol substituted), an optionally substituted benzophenone, an optionally substituted thiazole (preferably methyl and / or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted -(CH2)), an optionally substituted benzofuran, an optionally substituted thiophene ... benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an optionally substituted benzophenone, an m -O-C1-C6 alkyl group or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl group substituted 1,2,3-triazole), optionally substituted pyridine (2-, 3, or 4-pyridine) or a group according to the following chemical structure: [ka] where: S c is CHR SS , N.R. URE , or O, R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group, -C≡CR a In this case, R ais H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0312] Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group, -C≡CR a In this case, R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0313] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moiety is encompassed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described herein above.

[0314] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isooctane, and benzothiazolyl. Examples include oxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane.

[0315] Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, and N-alkoxy nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is fused to a benzene or cyclohexane ring or to another heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.). The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is fused to a benzene or cyclohexane ring or to another heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0316] The term "cycloalkyl" can mean, but is in no way limited to, a monocyclic or polycyclic alkyl group or a monovalent group derived from a cycloalkane as defined herein, such as, but not limited to, a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can mean, but is in no way limited to, a monocyclic or polycyclic alkyl group and is substituted with one or more substituents, such as, but not limited to, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, while these common substituents have the same meaning as the definition of the corresponding group defined in this description.

[0317] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, and P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, and P, and the group includes one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, and sulfo, wherein these generic substituents have the same meaning as the corresponding groups defined herein.

[0318] The term "spirocycle" or "spirofused cycloalkyl" refers to a polycyclic alkyl group containing at least two rings, where the two rings share exactly one ring atom. The term "spiroheterocycle" or "spirofused heterocycloalkyl" refers to a spirofused cycloalkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, and P. Spirofused cycloalkyl groups and spirofused heterocycloalkyl groups may be further defined by the number of rings, e.g., bicyclic, tricyclic, tetracyclic, etc.

[0319] The term "bridged cycloalkyl" refers to a polycyclic alkyl group containing at least two rings, wherein the two rings share at least three ring atoms. The term "bridged heterocycle" refers to a bridged cycloalkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, and P. Bridged cycloalkyl groups and spiro-fused heterocycloalkyl groups may be further defined by the number of rings, e.g., bicyclic, tricyclic, tetracyclic, etc.

[0320] "Halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0321] "C1-C6 alkyl" refers to a straight or branched chain saturated hydrocarbon containing from 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.

[0322] As used herein with respect to compounds of the present disclosure, "pharmaceutically acceptable salts" refers to salt forms of compounds of the present disclosure and hydrate forms of salts in which one or more water molecules are present. Such salt and hydrate forms retain the biological activity of the compounds of the present disclosure and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, edetate calcium salt, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine salt, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, and laurate. , magnesium salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0323] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, salts of the compounds of the present disclosure may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0324] Compounds of the present disclosure can exist in unsolvated as well as solvated forms, such as, for example, hydrated forms.

[0325] "Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a substance in which water maintains its molecular state as HO, and such combinations can form one or more hydrates. In hydrates, water molecules are bonded through subvalent bonds by intermolecular forces, particularly hydrogen bonds. Solid hydrates contain water in a stoichiometric ratio as so-called water of crystallization, and in this case, the water molecules do not necessarily have to be equivalent in terms of their bonding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of the salts of the compounds of the present disclosure are also suitable.

[0326] As referred to herein, an "isotopic derivative" refers to a compound of the present disclosure that is isotopically enriched or labeled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in this application, compounds of the present disclosure include compounds that are isotopically enriched or labeled with one or more atoms, such as, for example, deuterium.

[0327] As used herein, "treating" refers to the management and care of a subject for the purpose of combating a disease, condition, or disorder, including reducing or alleviating the symptoms or complications of the disease, condition, or disorder, or eliminating the disease, condition, or disorder.

[0328] As used herein, the term "treating," unless otherwise indicated, means reversing, alleviating, or arresting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of "treating" as defined immediately above. For example, the terms "treat," "treating," and "treatment" can refer to a method of alleviating or arresting a particular disorder and / or one or more of its attendant symptoms.

[0329] As used herein, "subject" means a human or an animal (in the case of an animal, the subject may be a mammal). In one embodiment, the subject is a human. In one embodiment, the subject is a male.

[0330] Prostate cancer is the uncontrolled growth of cancerous cells in the prostate gland.In some embodiments, the prostate cancer is metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, prostate cancer that is naive to novel hormonal agents (NHA), castration-sensitive prostate cancer that is naive to novel hormonal agents (NHA), castration-resistant prostate cancer that is naive to novel hormonal agents (NHA), metastatic prostate cancer that is naive to novel hormonal agents (NHA), metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHA), or metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHA).

[0331] Metastatic prostate cancer, or metastatic cancer, refers to prostate cancer that has spread beyond the prostate to other parts of the body, such as the bones, lymph nodes, liver, lungs, or brain.

[0332] Castrate-resistant prostate cancer (or castration-resistant prostate cancer) is a type of prostate cancer that continues to grow even when the amount of testosterone in the body is reduced to very low levels.

[0333] Metastatic castration-resistant prostate cancer is a type of prostate cancer that has metastasized and continues to grow even when the amount of testosterone in the body has fallen to very low levels.

[0334] Castrate-sensitive prostate cancer (CSPC), or castrate or castration-sensitive prostate cancer, is prostate cancer that can be controlled by reducing the amount of androgen (male hormone) in the body (e.g., via castration) and / or that requires androgen to grow and stops growing in the absence of androgen. CSPC is also called androgen-dependent prostate cancer, androgen-sensitive prostate cancer, or hormone-sensitive prostate cancer (HSPC).

[0335] Metastatic castration-sensitive prostate cancer is a type of castration-sensitive prostate cancer that has metastasized and requires androgens to grow or can be controlled by reducing the amount of androgens in the body (e.g., via castration).

[0336] Novel hormone-naive (NHA) prostate cancer is prostate cancer that has not been previously treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0337] Novel hormone-naive (NHA)-naive metastatic prostate cancer is metastatic prostate cancer that has not previously been treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0338] Novel hormone-naive (NHA)-naive castration-resistant prostate cancer is castration-resistant prostate cancer that has not previously been treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0339] Novel hormonal agent (NHA)-naive castration-sensitive prostate cancer is castration-sensitive prostate cancer that has not previously been treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0340] Novel hormone-naive (NHA)-naive metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has not previously been treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0341] Novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer is metastatic castration-sensitive prostate cancer that has not previously been treated with a second-generation antiandrogen, such as an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the androgen biosynthesis inhibitor is abiraterone or abiraterone acetate. In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0342] As used herein, "preventing" refers to arresting the onset of symptoms or complications of a disease, condition, or disorder.

[0343] "Administration" refers to the introduction of a pharmaceutical agent, such as a compound of the present disclosure, into a subject. The related terms "administering" and "administration of" (and grammatical equivalents) refer to both direct administration, which can be administration to a subject by a medical professional or by the subject self-administering, and / or indirect administration, which can be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering a drug to the patient.

[0344] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a time that differs from the administration of the additional therapeutic agent(s)), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapeutic effects, including anti-cancer activity.

[0345] As used herein, "therapeutically effective amount" refers to an amount of the free base of a compound of the present disclosure, or an equivalent amount of a pharmaceutically acceptable salt of a compound of the present disclosure, sufficient to treat, ameliorate, or prevent a particular disease (e.g., prostate cancer), symptom, disorder, or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount for a particular subject may 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, which is within the skill and judgment of the clinician.

[0346] 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 the compound to the subject.

[0347] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to the compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng*H / mL (ngxH / mL), where "H" refers to time.

[0348] As used herein, "AUC tau " refers to the AUC from time 0 to the end of the dosing interval.

[0349] "AUC 0-24 " means the AUC from 0 hours to 24 hours after administration of a single dose.

[0350] As used herein with respect to oral dosage forms, "controlled release" or "CR" refers to when a compound of the disclosure is released from the dosage form according to a predetermined profile, which may include when and where release occurs, and / or according to a particular rate of release over a particular period of time, following oral administration.

[0351] As used herein with respect to oral dosage forms of the present disclosure, "release-controlling agent" refers to one or more substances or materials that modify the release of a compound of the present disclosure from the dosage form. Controlled-release agents can be organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, and combinations thereof.

[0352] 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 a compound of the present disclosure and that remains substantially intact in the acidic environment of the stomach but dissolves in the pH environment of the intestine.

[0353] "Gastric acid-resistant" or "GR" as applied to the CR oral dosage forms described herein means that the release of a compound of the disclosure in the stomach of a subject shall not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of compound of the disclosure in the dosage form.

[0354] As used herein, "oral dosage form" refers to a pharmaceutical preparation containing a specific amount (dose) of a compound of the present disclosure or a pharmaceutically acceptable salt and / or solvate thereof as the active ingredient and inactive ingredients (excipients), and formulated into a specific external form suitable for oral administration, such as an oral tablet, liquid, or capsule. In some embodiments, the composition is in the form of a tablet that can be divided.

[0355] As used in this disclosure, the term "carrier" encompasses pharmaceutically acceptable excipients and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or body part to another organ or body part of a subject.

[0356] The term "about" as part of a quantitative expression, e.g., "about X," includes any value 10% higher or lower than X, and also includes any value between X-10% and X+10%. Thus, for example, a weight of about 40 g includes a weight of 36 to 44 g. When used herein to refer to amino acid residues of AR, the term "about" refers to any amino acid residue within 5 amino acid residues of the specified one. For example, when referring to a contiguous stretch of amino acid residues spanning from about amino acid residue 560 to about amino acid residue 624 of AR, this refers to a contiguous stretch of amino acid residues spanning from amino acid residue 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, or 565 of AR of SEQ ID NO: 1 to amino acid residue 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, or 629 of AR of SEQ ID NO: 1. In some embodiments, the term "about" refers to any amino acid residue within 3 amino acid residues of what is specified. In some embodiments, the term "about" refers to any amino acid residue within 1 amino acid residue of what is specified.

[0357] Compound A of the present disclosure is 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, having the following structure: [ka]

[0358] In some embodiments, Compound A can be prepared as described in U.S. Patent Application Publication No. 2021 / 0196710A1, which is incorporated herein by reference.

[0359] "Comprising" or "comprising," 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 the specific description or claim, but does not exclude other elements. "Consisting essentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the recited physical, pharmacological, pharmacokinetic properties or therapeutic efficacy of the composition, dosage form, method, use, or process. "Consisting of" and "consisting of" mean excluding all but trace elements of other ingredients and all but substantial method or process steps.

[0360] The ECOG performance status scale was developed by the Eastern Cooperative Oncology Group as a standard measure of how disease affects a patient's ability to perform daily activities. It describes a patient's level of function in terms of their ability to care for themselves, perform daily activities, and physical abilities (walking, working, etc.). Patients are classified on a scale of 1 to 5: [Table 1]

[0361] "Fasted conditions" or "fasted state," as used to describe a subject, means that the subject has not eaten for at least 4 hours prior to the time of interest, e.g., the time of administration of a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof). In embodiments, a subject in a fasted state has not eaten for at least 6, 8, 10, or 12 hours prior to administration of a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof).

[0362] As used herein to describe a subject, "fed condition" or "fed state" means that the subject has eaten less than 4 hours prior to the time of interest, e.g., the time of administration of a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof). In embodiments, a fed subject has eaten within any of at least 3, 2, 1, or 0.5 hours prior to administration of a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof).

[0363] Corticosteroids are a class of steroid hormones that include both steroid hormones produced in humans and other vertebrates and their synthetic derivatives or analogs. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the corticosteroid is a mineralocorticoid. In some embodiments, the corticosteroid is prednisone, prednisolone, methylprednisolone, cortisone, cortisol, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

[0364] "Proton pump inhibitor" or "PPI" refers to a member of a class of compounds that reduce or eliminate acid production in the stomach. In some embodiments, the PPI is omeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole, or rabeprazole.

[0365] "H2 antagonists" or "H2 receptor blockers," collectively referred to herein as "H2 compounds," refer to members of a class of compounds that reduce or prevent histamine-induced gastric acid secretion in the stomach. In some embodiments, the H2 compound is ranitidine, famotidine, nizatidine, or cimetidine.

[0366] As used herein, "gastric acid modifiers" refers collectively to PPIs, H2 compounds, and antacids, including those prescribed by physicians and those available over the counter.

[0367] As used herein, the term "CDK inhibitor" refers to a compound that inhibits human enzymes called cyclin-dependent kinases (CDKs). In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. As used herein, the term "CDK4 / 6 inhibitor" refers to a compound that inhibits CDK4 and / or 6. Examples of CDK inhibitors include, but are not limited to, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In some embodiments, the CDK inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0368] As used herein, the term "PARP inhibitor" refers to a compound that inhibits a human enzyme called poly ADP-ribose polymerase (PARP). Examples of PARP inhibitors include, but are not limited to, olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP9722, E7016, 3-aminobenzamide, mefparib, and AZD2281.

[0369] As used herein, the term "anticancer agent" is used to refer to an anticancer agent, or a therapeutic agent administered simultaneously with an anticancer agent (e.g., palonosetron), with which a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) may be co-administered and / or co-formulated to treat cancer and side effects associated with cancer treatment. These agents include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CDK inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubican, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,Doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, estrogen, erythropoietin, erythroxine, riboflavin ... Xemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258), 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide , megestrol acetate, CP-724714, TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Calmette-Guérin Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine,Melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-c is-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mechatoprine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS- 275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, Cremov All-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronic acid, prednisone, cetuximab,Granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans-retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, These include arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In some embodiments, the anticancer agent is selected from the group consisting of abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, and zoledronic acid. In some embodiments, the anticancer agent is selected from the group consisting of an FLT-3 inhibitor, an androgen receptor inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an Aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-Met inhibitor, a PARP inhibitor, a CDK4 / 6 inhibitor, an anti-HGF antibody, an IGFR TK inhibitor, a PI3 kinase inhibitor, an AKT inhibitor, a JAK / STAT inhibitor, a checkpoint 1 inhibitor, a checkpoint 2 inhibitor, a focal adhesion kinase inhibitor, a MAP kinase inhibitor,VEGF trap antibodies, and chemical castration agents.

[0370] In some embodiments, the anticancer agent is temozolomide, capecitabine, irinotecan, tamoxifen, anastrazole, eximestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroprogesterone caproate. caproate), raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, arzoxifene, fulvestrant, prednisone, abiraterone, abiraterone acetate, enzalutamide, apalutamide, darolutamide, sipuleucel-T, pembrolizumab, nivolumab, cemiplimab, atezolizumab (Tecen triq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, and zoledronic acid.

[0371] Abiraterone acetate, i.e., [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]acetate, is a commercially available drug developed by Janssen and sold under the brand name Zytiga®, indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. The structure of abiraterone acetate is: [ka] is.

[0372] Abiraterone, i.e., (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, is the active metabolite of abiraterone acetate and has the following structure: [ka]

[0373] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0374] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0375] 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 rhesus monkey.

[0376] In some embodiments, the subject is a human.

[0377] In some embodiments, the subject is a human diagnosed with prostate cancer.

[0378] In some embodiments, the subject is a human diagnosed with metastatic prostate cancer.

[0379] In some embodiments, the subject is a human diagnosed with castration-resistant prostate cancer.

[0380] In some embodiments, the subject is a human diagnosed with metastatic castration-resistant prostate cancer.

[0381] In some embodiments, the subject is a human diagnosed with castration-sensitive prostate cancer.

[0382] In some embodiments, the subject is a human diagnosed with metastatic castration-sensitive prostate cancer.

[0383] In some embodiments, the subject is a human diagnosed with novel hormonal agent (NHA) naive prostate cancer.

[0384] In some embodiments, the subject is a human diagnosed with castration-sensitive prostate cancer that is naive to novel hormonal agents (NHA).

[0385] In some embodiments, the subject is a human diagnosed with castration-resistant prostate cancer that is naive to novel hormonal agents (NHA).

[0386] In some embodiments, the subject is a human diagnosed with metastatic prostate cancer that is novel hormonal agent (NHA) naive.

[0387] In some embodiments, the subject is a human diagnosed with metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0388] In some embodiments, the subject is a human diagnosed with metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs).

[0389] Compounds of the Disclosure In one aspect, the present application relates to bifunctional or multifunctional compounds useful for modulating protein activity by inducing target protein degradation. In some embodiments, the bifunctional compounds comprise an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety, preferably linked via a linker moiety, as specifically described herein, wherein the E3 ubiquitin ligase-binding moiety is linked to the protein-targeting moiety, the E3 ubiquitin ligase-binding moiety recognizes a protein of the ubiquitin pathway (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), the protein-targeting moiety recognizes a target protein, and degradation of the target protein occurs when the target protein is brought into proximity with the ubiquitin ligase, resulting in degradation / inhibition of the target protein's action and control of protein levels. In certain embodiments, the bifunctional compounds comprise a CLM and a PTM linked, for example, covalently, directly, or indirectly, to a chemical linker L, which may be depicted as follows: PTM-L-CLM

[0390] The CLM recognizes and binds to the E3 ubiquitin ligase cereblon. The PTM is a small protein-binding moiety that binds to and recruits target proteins or polypeptides within cells, bringing them into proximity with the CLM for degradation of the target protein, resulting in ubiquitination of the target protein. In certain embodiments, the PTM is an AR-binding moiety (ABM).

[0391] In any of the compounds described herein, the PTM comprises the following chemical structure: [ka] [ka]

[0392] In any of the compounds described herein, the L comprises the following chemical structure: [ka] [ka]

[0393] In any of the compounds described herein, the CLM comprises the following chemical structure: [ka] [ka]

[0394] In another aspect, the present application provides a compound having the structure: ABM-L-CLM or a pharmaceutically acceptable salt thereof, where: (a) ABM is an androgen receptor (AR) binding moiety having the following structure: [ka] where: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently 1 , or N, [ka] is a 4- to 6-membered cycloalkyl, C6-C 10 aryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl contains 0 to 4 heteroatoms; Q 6 , Q 7 , Q 8 , Q 9 , and Q 10 are each independently 3 , or N, Each R 1are independently selected from the group consisting of H, optionally substituted straight chain or branched C1-C6 alkyl, cyano, halogen, and optionally substituted straight chain or branched C1-C6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with one or more halo; Each R 2 is independently selected from the group consisting of optionally substituted straight chain or branched C1-C6 alkyl, cyano, halogen, and optionally substituted straight chain or branched C1-C6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with one or more halo; Each R 3 are independently selected from the group consisting of H, optionally substituted straight chain or branched C1-C6 alkyl, cyano, halogen, and optionally substituted straight chain or branched C1-C6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with one or more halo; n is 0, 1, 2, 3, or 4; (b) L is a chemical linking moiety having the structure: [ka] where: the ABM is linked to W and the CLM is linked to Z; or the ABM is linked to Z and the CLM is linked to W; W is absent or [ka] and [ka] is a 4- to 7-membered cycloalkyl, a 4- to 7-membered heterocycle, or a spiro-bicyclic heterocycloalkyl, wherein each ring of the spiro-bicycle is 4- to 7-membered; X is -CH2- or absent; Y is -NR 6 -, -O- or absent, [ka] is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle, Z is -C(R 7 )2-, -NR 7 -, -O- or absent, R 6 is H, linear or branched C 1-6 Alkyl, linear or branched C 1-6 Alkoxy-C 1-6 alkyl, or [ka] and [ka] indicates a bond to Y, [ka] teeth, [ka] indicates the bond to Each R 7 are independently H, straight chain or branched C 1-6 Alkyl and straight or branched C 1-6 alkoxy; p is 1, 2, 3, or 4; q is 1, 2, 3, 4, or 5; (c) CLM is a cereblon E3 ubiquitin ligase binding moiety having the following structure: [ka] where: [ka] is C6-C 10 aryl, 4- to 7-membered heteroaryl, or bridged bicyclic cycloalkyl; [ka] indicates that the linking moiety L is connected to the ring S by one or two covalent bonds; Each R 4 is independently selected from the group consisting of optionally substituted straight chain or branched C1-C6 alkyl, cyano, halogen, and optionally substituted straight chain or branched C1-C6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with one or more halo; R 5 is H, optionally substituted straight chain or branched C1-C6 alkyl, or optionally substituted straight chain or branched C1-C6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with one or more halo; m is 0, 1, 2, 3, or 4.

[0395] In another aspect, the present application provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0396] In some embodiments, [ka] is pyridyl, [ka] is tetramethylcyclobutyl, and Q 2 is CR 1 and Q 4 is CR 1 If R 1 is not Chrollo.

[0397] In some embodiments, the compound of Formula (I) is not N-(4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide.

[0398] In some embodiments, the compound of formula (I) is [ka] isn't it.

[0399] In some embodiments, L is [ka] where: [ka] is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle, Y is -NR 6 -, -O- or absent, R 6 is H, linear or branched C 1-6 Alkyl, or straight or branched C 1-6 is an alkoxy, [ka] is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle.

[0400] In some embodiments, L is [ka] where: [ka] is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle, Y is -NR 6- or -O-, R 6 is H, linear or branched C 1-6 Alkyl, or straight or branched C 1-6 is an alkoxy, [ka] is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle.

[0401] In some embodiments, L is [ka] where: [ka] is piperidinyl or morpholinyl, Y is -NR 6 - or -O-, R 6 teeth, [ka] and [ka] is cyclobutyl, Z is —O—.

[0402] In some embodiments, L is [ka] where: [ka] is piperidinyl or morpholinyl, [ka] is piperazinyl.

[0403] In some embodiments, [ka] is piperidinyl.

[0404] In some embodiments, the compound is a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0405] In some embodiments, the compound is a compound of Formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0406] In some embodiments, Q 1 ~Q 5 are respectively CR 1 In some embodiments, Q 1 ~Q 5 In some embodiments, one to three of Q 1 ~Q 5 Exactly one of Q is N. In some embodiments, Q 1 ~Q 5 Exactly two of Q are N. In some embodiments, Q 1 ~Q 5 Exactly three of them are N.

[0407] In some embodiments, Q 6 ~Q 10 are respectively CR 1 In some embodiments, Q 6 ~Q 10 In some embodiments, one to three of Q 6 ~Q 10Exactly one of Q is N. In some embodiments, Q 6 ~Q 10 Exactly two of Q are N. In some embodiments, Q 6 ~Q 10 Exactly three of them are N.

[0408] In some embodiments, Q 1 is CH and Q 2 is C(CH3) and Q 3 is C(CN) and Q 4 is C(CH3) and Q 5 is CH.

[0409] In some embodiments, Q 1 is CH and Q 2 is C(OCH3) and Q 3 is C(CN) and Q 4 is CH and Q 5 is CH.

[0410] In some embodiments, Q 1 is CH and Q 2 is C(Cl) and Q 3 is C(CN) and Q 4 is CH and Q 5 is CH.

[0411] In some embodiments, R 1 is selected from the group consisting of H, CN, and CH. In some embodiments, R 1 are H, CN, and OCH 3 In some embodiments, R 1 is selected from the group consisting of H, CN, and Cl. In some embodiments, at least one R is CF.

[0412] In some embodiments, [ka] is a 4-6 membered cycloalkyl. In some embodiments, [ka] is cyclobutyl or cyclohexyl. In some embodiments, [ka] is cyclobutyl. In some embodiments, [ka] is cyclopentyl. In some embodiments, [ka] is cyclohexyl.

[0413] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0414] In some embodiments, R 2 is a straight chain or branched C1-C6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R2 is pentyl. In some embodiments, R 2 is hexyl.

[0415] In some embodiments, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, [ka] is phenyl. In some embodiments, [ka] is pyridinyl. In some embodiments, [ka] is pyridazinyl. In some embodiments, [ka] is pyrimidinyl. In some embodiments, [ka] is pyrazinyl.

[0416] In some embodiments, each R 4 is independently selected from the group consisting of F, methoxy, ethoxy, methyl, and ethyl. In some embodiments, each R 4 is independently selected from the group consisting of F, methoxy, and methyl. In some embodiments, R 4 is F.

[0417] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0418] In one aspect, the present application relates to a compound of formula (Id) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0419] In one aspect, the present application relates to a compound of formula (Ie) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0420] In one aspect, the present application relates to a compound of formula (If) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0421] In one aspect, the present application relates to a compound of formula (Ig) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0422] In one aspect, the present application relates to a compound of formula (Ih) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0423] In one aspect, the present application relates to a compound of formula (Ii) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0424] In one aspect, the present application relates to a compound of formula (Ij) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0425] In one aspect, the present application relates to a compound of formula (Ik) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0426] In one aspect, the present application relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0427] In one aspect, the present application relates to a compound of formula (Im) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0428] In one aspect, the present application relates to a compound of formula (Io) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0429] In one aspect, the present application relates to a compound of formula (Ip) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0430] In one aspect, the present application relates to a compound of formula (Iq) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0431] In one aspect, the present application relates to a compound of formula (Ir) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0432] In one aspect, the present application relates to a compound of formula (Is) or a pharmaceutically acceptable salt thereof: [ka] wherein all variables are as defined herein.

[0433] In some embodiments, the compound of the present disclosure is Compound A, i.e., 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, having the following structure: [ka]

[0434] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, which can be obtained in light of this disclosure from the relevant scientific literature or from standard reference texts in the field. Recognized reference texts for organic synthesis include, but are not limited to, Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001, and Greene, TW; Wuts, PGMProtective Groups in Organic Synthesis, 3. rd John Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2018 / 0099940 and WO 2018 / 144649 are incorporated herein by reference in their entireties.

[0435] In some embodiments, compounds of the present disclosure can be prepared according to the procedures and methods disclosed herein, including, for example, those shown in Table 1. Other bifunctional compounds of the present disclosure can be prepared using similar methods from common intermediates or their derivatives.

[0436] A method for ubiquitinating and degrading target proteins in cells The present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. The method comprises administering a bifunctional composition comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker moiety, as specifically described herein, wherein the E3 ubiquitin ligase binding moiety is linked to the protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a protein in the ubiquitin pathway (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), the protein targeting moiety recognizes a target protein, and degradation of the target protein occurs when the target protein is brought into proximity with the ubiquitin ligase, resulting in degradation / inhibition of the target protein's action and control of protein levels. The control of protein levels provided by the present disclosure reduces the level of the target protein in a patient's cells, thereby providing treatment for a disease state or condition regulated via the target protein.

[0437] In one aspect, the present application provides a compound of formula (I) or its pharmaceutically acceptable salt, which degrades androgen receptor (AR) protein.In some embodiments, the AR degraded by the compound of formula (I) is wild-type AR.In some embodiments, the AR degraded by the compound of formula (I) is mutant AR.

[0438] As those skilled in the art will understand, AR has a modular structure, comprising three functional domains: N-terminal transcriptional regulatory domain, DNA binding domain, and ligand binding domain (MacLean HE, et al. J.Steroid Biochem Mol Biol. (1997) 62:233-42).The DNA binding domain is linked to the ligand binding domain via a hinge.The AR ligand binding domain refers to the functional domain of human AR, which folds to form a hydrophobic pocket that binds to AR cognate hormone ligand (e.g., androgen).

[0439] Furthermore, it is understood in the art that AR is 920 amino acid residues long, and the N-terminal transcriptional regulatory domain extends from amino acid residue 1 to about amino acid residue 559, the DNA binding domain extends from amino acid residue 560 to about amino acid residue 624, the hinge extends from amino acid residue 625 to about amino acid residue 676, and the ligand binding domain extends from amino acid residue 677 to about amino acid residue 920. Suitable AR reference sequence is represented by SEQ ID NO: 1 and is identified as P10275 (ANDR_HUMAN) in UniProt database. The gene encoding AR ("AR gene") is approximately 90kb and has chromosomal coordinates 67544021-67730619 according to human reference genome GRCh38.p13. The AR gene contains eight exons: exon 1 encodes the N-terminal transcriptional regulatory domain, exons 2-3 encode the DNA-binding domain, and exons 4-8 encode the hinge and ligand-binding domain (Jenster, et al. (1992) J. Steroid Biochem. Mol. Biol. 41:671-75).

[0440] In some embodiments, the subject has prostate cancer comprising at least one somatic AR tumor mutation in the functional domain of AR. In some embodiments, the at least one somatic AR tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues in the functional domain of AR compared to an AR reference sequence (e.g., SEQ ID NO: 1). In some embodiments, the at least one somatic AR tumor mutation is a substitution of one or more amino acid residues in the functional domain of AR compared to an AR reference sequence (e.g., SEQ ID NO: 1). In some embodiments, the at least one somatic AR tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues in the ligand-binding domain of the AR compared to an AR reference sequence (e.g., SEQ ID NO: 1). In some embodiments, the at least one somatic AR tumor mutation is a substitution of one or more amino acid residues in the ligand-binding domain of the AR compared to an AR reference sequence (e.g., SEQ ID NO: 1). In some embodiments, the at least one somatic AR tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues selected from amino acid residues 677-920 compared to an AR reference sequence, wherein the AR reference sequence is set forth by SEQ ID NO: 1. In some embodiments, the at least one somatic AR tumor mutation is a substitution of one or more amino acid residues selected from amino acid residues 677-920 compared to an AR reference sequence, wherein the AR reference sequence is set forth by SEQ ID NO:1.

[0441] In some embodiments, alterations (e.g., substitutions) of amino acid residues in the AR ligand-binding domain result in mutant ARs with reduced ligand specificity and / or improved cofactor recruitment. Without being bound by theory, mutant ARs with reduced ligand specificity and / or improved cofactor recruitment have increased potency in triggering the AR signaling pathway, thereby conferring a growth advantage to tumor cells containing the mutant AR.

[0442] In some embodiments, the prostate cancer comprises cancer cells characterized by the expression of at least one somatic AR tumor mutation described herein.Methods for identifying cancers characterized by the expression of somatic mutations are known in the art, and include, for example, obtaining a biological sample from a subject, collecting the biological sample to obtain genetic material (e.g., genomic DNA or RNA), and performing sequence analysis, RNA sequence analysis, or real-time polymerase chain reaction (RT-PCR).For example, in some embodiments, first, obtain genomic DNA (using any standard technique) from cancerous tissue obtained from a subject, prepare cDNA, and amplify (e.g., using polymerase chain reaction) to obtain a sufficient amount of cDNA for sequence analysis, and perform sequencing, for example, using next-generation sequencing.Genomic DNA or RNA is usually extracted from a biological sample, for example, tissue removed from a subject by tissue biopsy. In some embodiments, the biological sample is a tissue biopsy sample (e.g., a prostate biopsy sample), in which case genomic DNA or RNA sequencing is performed to determine the presence of a somatic mutation in AR (e.g., a somatic mutation resulting in a substitution of an amino acid residue in the AR ligand-binding domain). In some embodiments, the biological sample comprises plasma obtained from the subject and is used to detect somatic AR tumor mutations present in circulating tumor DNA, for example, using PCR-based amplification followed by gene sequencing.

[0443] In some embodiments, the mutant form of AR that is degraded by a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises at least one AR somatic tumor mutation.

[0444] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, and E898X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, and E898X, wherein "X" is selected from alanine (A), valine (V), leucine (L), isoleucine (I), thiamin (H), thiamin (T), thiamin (V), thiamin (T ... "Amino acid" refers to an amino acid residue other than the wild-type residue at that position selected from: phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0445] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, T878X, H875X, W742X, F877X, V716X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, T878X, H875X, W742X, F877X, V716X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0446] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, T878X, and H875X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702X, T878X, and H875X, wherein "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0447] In some embodiments, the at least one somatic AR tumor mutation is L702X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is L702X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0448] In some embodiments, the at least one somatic AR tumor mutation is T878X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is T878X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is T878X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A) and serine (S). In some embodiments, the at least one somatic AR tumor mutation is T878A. In some embodiments, the at least one somatic AR tumor mutation is T878A.

[0449] In some embodiments, the at least one somatic AR tumor mutation is H875X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is H875X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is H875Y.

[0450] In some embodiments, the at least one somatic AR tumor mutation is not selected from any one or any combination of L702X, T878X, and H875X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is not selected from any one or any combination of L702X, T878X, and H875X, wherein "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0451] In some embodiments, the at least one somatic AR tumor mutation is not L702X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is not L702X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is not L702H.

[0452] In some embodiments, the at least one somatic AR tumor mutation is not T878X, and "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is not T878X, and "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is not T878X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A) and serine (S). In some embodiments, the at least one somatic AR tumor mutation is not T878A. In some embodiments, the at least one somatic AR tumor mutation is not T878A.

[0453] In some embodiments, the at least one somatic AR tumor mutation is not H875X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic AR tumor mutation is not H875X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E). In some embodiments, the at least one somatic AR tumor mutation is not H875Y.

[0454] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, and E898G.

[0455] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of L702H, T878A, H875Y, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, M895X, M896X, and S889G. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of E666K, Q799E, Q793E, Q118K, Y447N, S532Y, G751C, Q825E, L702H, T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of E666K, Q799E, Q793E, Q118K, Y447N, S532Y, G751C, Q825E, T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G.

[0456] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, M895X, M896X, and S889G. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of H875Y, H875L, T878A, F877L, V716M, T878S, W742C, and W742L. In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of H875Y, H875L, Q825E, T878A, F877L, V716M, T878S, W742C, and W742L. In some embodiments, the at least one somatic AR tumor mutation is L702H. In some embodiments, the at least one somatic AR tumor mutation is T878A. In some embodiments, the at least one somatic AR tumor mutation is H875Y. In some embodiments, the at least one somatic AR tumor mutation is H875L. In some embodiments, the at least one somatic AR tumor mutation is Q825E. In some embodiments, the at least one somatic AR tumor mutation is W742C. In some embodiments, the at least one somatic AR tumor mutation is W742L. In some embodiments, the at least one somatic AR tumor mutation is F877L. In some embodiments, the at least one somatic AR tumor mutation is T878S. In some embodiments, the at least one somatic AR tumor mutation is V716M. In some embodiments, the at least one somatic AR tumor mutation is D891H. In some embodiments, the at least one somatic AR tumor mutation is M750V. In some embodiments, the at least one somatic AR tumor mutation is M750T. In some embodiments, the at least one somatic AR tumor mutation is S889G.

[0457] In some embodiments, the at least one somatic AR tumor mutation is selected from L702H, T878A, H875Y, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G.

[0458] In some embodiments, the at least one somatic AR tumor mutation is selected from L702H, M895V, W742C, S889G, M750V, M896V, T878A, T878S, F877L, D891H, H875Y, and any combination thereof.

[0459] In some embodiments, the mutant form of AR that is resolved by a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises at least two AR somatic tumor mutations.

[0460] In some embodiments, the at least two somatic AR tumor mutations are selected from L702H, M895V, W742C, S889G, M750V, M896V, T878A, T878S, F877L, D891H, H875Y, and any combination thereof.

[0461] In some embodiments, the mutant form of AR degraded by the compound of formula (I) comprises at least two AR somatic tumor mutations.

[0462] In some embodiments, the at least two somatic AR tumor mutations are selected from L702X, T878X, H875X, W742X, F877X, V716X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least two somatic AR tumor mutations are selected from L702X, T878X, H875X, W742X, F877X, V716X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0463] In some embodiments, the at least two somatic AR tumor mutations are selected from L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, and E898X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least two somatic AR tumor mutations are selected from L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, and E898X, wherein "X" is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (V), phenylalanine (P), phenylalanine (Y ... It refers to an amino acid residue other than the wild-type residue at that position selected from lanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0464] In some embodiments, the at least two somatic AR tumor mutations are selected from H875X, Q825X, T878X, F877X, V716X, T878X, W742X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least two somatic AR tumor mutations are selected from H875X, Q825X, T878X, F877X, V716X, T878X, W742X, D891X, M750X, M895X, M896X, and S889X, where "X" refers to an amino acid residue other than the wild-type residue at that position selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0465] In some embodiments, the at least two somatic AR tumor mutations are selected from L702H, T878A, H875Y, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, M895X, M896X, and S889G. In some embodiments, the at least two somatic AR tumor mutations are selected from E666K, Q799E, Q793E, Q118K, Y447N, S532Y, G751C, Q825E, L702H, T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G. In some embodiments, the at least two somatic AR tumor mutations are selected from E666K, Q799E, Q793E, Q118K, Y447N, S532Y, G751C, Q825E, T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G.

[0466] In some embodiments, the at least two somatic AR tumor mutations are selected from L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, and E898G.

[0467] In some embodiments, the at least two somatic AR tumor mutations are selected from T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, M895X, M896X, and S889G. In some embodiments, the at least two somatic AR tumor mutations are selected from H875Y, H875L, T878A, F877L, V716M, T878S, W742C, and W742L. In some embodiments, the at least two somatic AR tumor mutations are selected from H875Y, H875L, Q825E, T878A, F877L, V716M, T878S, W742C, and W742L.

[0468] In some embodiments, the at least two somatic AR tumor mutations are selected from L702H, H875Y, T878A, F877L, V716M, T878S, W742C, and W742L.

[0469] In some embodiments, the at least two somatic AR tumor mutations are selected from the following group of mutations: L702H and H875Y, L702H, T878A, and H875Y, T878A, F877L, L702H, and V716M, T878S and H875Y, T878S and W742C, W742C and W742L, and L702H and T878A.

[0470] In some embodiments, the at least two somatic AR tumor mutations are selected from the following group of mutations: L702H and H875Y, L702H, T878A, and H875Y, H875L and Q825E, T878A, F877L, and V716M, T878A, L702H, M750T, and D891H, T878S and H875Y, T878A and T878S, T878S and W742C, W742C and W742L, and L702H and T878A.

[0471] In some embodiments, the at least two somatic AR tumor mutations are selected from the following group of mutations: T878A and H875Y, H875L and Q825E, T878A, F877L, and V716M, T878A, M750T, and D891H, T878S and H875Y, T878A and T878S, T878S and W742C, W742C and W742L.

[0472] In some embodiments, the somatic AR tumor mutation(s) is / are selected from the group of the following mutation(s): L702H, T878A, T878S, H875Y, L702H and T878A, L702H and T878S, L702H and H875Y, T878A and H875Y, T878S and H875Y, L702H, T878A, and H875Y, and L702H, T878S, and H875Y.

[0473] In some embodiments, the somatic AR tumor mutation is not selected from one of the following group of mutation(s): L702H, T878A, T878S, H875Y, L702H and T878A, L702H and T878S, L702H and H875Y, T878A and H875Y, T878S and H875Y, L702H, T878A, and H875Y, and L702H, T878S, and H875Y.

[0474] In some embodiments, the somatic AR tumor mutation is a missense mutation(s) in the AR ligand binding domain (LBD) that is not selected from one of the following group of mutation(s): L702H, T878A, T878S, H875Y, L702H and T878A, L702H and T878S, L702H and H875Y, T878A and H875Y, T878S and H875Y, L702H, T878A, and H875Y, and L702H, T878S, and H875Y.

[0475] In some embodiments, the present disclosure is directed to a method of treating a patient in need of treatment for a disease state or condition regulated through a protein, where degradation of the protein provides a therapeutic benefit to the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with another anti-cancer agent. The disease state or condition may be a disease caused by a microbial agent or other foreign agent, such as a virus, bacteria, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that results in the disease state and / or condition.

[0476] Treatment method In one aspect, the present application relates to a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, preferably Compound A, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0477] In one aspect, the present application relates to a method for preventing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, preferably Compound A, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotopic derivative thereof.

[0478] In one aspect, the present application relates to a method for treating and / or preventing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0479] In one aspect, the present application relates to a method for treating and / or preventing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, in combination with one or more additional anti-cancer agents.

[0480] In one aspect, the present application relates to a method for treating and / or preventing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0481] In one aspect, the present application relates to a method for treating and / or preventing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with one or more additional anti-cancer agents.

[0482] The methods of treating cancer described herein result in a reduction in tumor size. Alternatively, or in addition, the cancer is metastatic cancer and the methods of treatment include inhibiting invasion of metastatic cancer cells.

[0483] In some embodiments, the cancer is prostate cancer.

[0484] In some embodiments, the cancer is prostate adenocarcinoma.

[0485] In some embodiments, the cancer is metastatic prostate cancer.

[0486] In some embodiments, the cancer is castration-resistant prostate cancer.

[0487] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0488] In some embodiments, the cancer is advanced mCRPC.

[0489] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0490] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0491] In some embodiments, the prostate cancer is novel hormonal agent (NHA) naive prostate cancer.

[0492] In some embodiments, the prostate cancer is novel hormonal agent (NHA) naive metastatic prostate cancer.

[0493] In some embodiments, the prostate cancer is castration-resistant prostate cancer that is naive to novel hormonal agents (NHA).

[0494] In some embodiments, the prostate cancer is castration-sensitive prostate cancer that is naive to novel hormonal agents (NHA).

[0495] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0496] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs).

[0497] In some embodiments, the prostate cancer is not novel hormonal agent (NHA) naive prostate cancer. In some embodiments, the prostate cancer that is not novel hormonal agent (NHA) naive prostate cancer is also metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0498] In some embodiments, the subject has been diagnosed with histologically, pathologically, or cytologically confirmed prostate adenocarcinoma.

[0499] In some embodiments, the subject with prostate cancer (e.g., mCRPC) is also undergoing ongoing androgen deprivation therapy (ADT). In some embodiments, ADT comprises administering to the subject a gonadotropin-releasing hormone analog or inhibitor. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is leuprolide, goserelin, triptorelin, histrelin, leuprolide mesylate, or a pharmaceutically acceptable salt thereof. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is leuprolide. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is leuprolide mesylate. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is goserelin. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is goserelin acetate. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is triptorelin. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is triptorelin acetate. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is triptorelin pamoate. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is histrelin. In some embodiments, the gonadotropin-releasing hormone analog or inhibitor is histrelin acetate. In some embodiments, the subject has undergone orchiectomy.

[0500] In some embodiments, the subject has undergone at least one previously approved systemic therapy for metastatic prostate cancer and experienced prostate cancer progression prior to administration of a therapeutically effective amount of the bifunctional compound of the present disclosure. In some embodiments, the subject has undergone at least two previously approved systemic therapies for metastatic prostate cancer and experienced prostate cancer progression prior to administration of a therapeutically effective amount of the bifunctional compound of the present disclosure. In some embodiments, at least one of the previously approved systemic therapies for metastatic prostate cancer is a second-generation androgen inhibitor. In some embodiments, the subject has undergone at least two previously approved systemic therapies for metastatic prostate cancer and experienced prostate cancer progression prior to administration of a therapeutically effective amount of the bifunctional compound of the present disclosure, at least one of which is a second-generation androgen inhibitor. In some embodiments, the second-generation androgen inhibitor is abiraterone, abiraterone acetate, enzalutamide, darolutamide, apalutamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the second-generation androgen inhibitor is abiraterone. In some embodiments, the second-generation androgen inhibitor is abiraterone acetate. In some embodiments, the second-generation androgen inhibitor is enzalutamide. In some embodiments, the second-generation androgen inhibitor is darolutamide. In some embodiments, the second-generation androgen inhibitor is apalutamide.

[0501] In some embodiments, the subject has been administered at least one but no more than three previous second-generation antiandrogens (e.g., enzalutamide, abiraterone acetate, abiraterone, darolutamide, or apalutamide) prior to administration of a therapeutically effective amount of a bifunctional compound of the present disclosure. In some embodiments, the subject has been administered one previous second-generation antiandrogen. In some embodiments, the subject has been administered two previous second-generation antiandrogens. In some embodiments, the subject has been administered three previous second-generation antiandrogens.

[0502] In some embodiments, the subject has undergone two or less previous chemotherapy regimens before administering a therapeutically effective amount of the bifunctional compound of the present disclosure.In some embodiments, the subject has undergone two previous chemotherapy regimens.In some embodiments, the subject has undergone one previous chemotherapy regimen.In some embodiments, the subject has not undergone any previous chemotherapy regimen.

[0503] In some embodiments, the subject has undergone two or less previous chemotherapy regimens before administering a therapeutically effective amount of the bifunctional compound of the present disclosure (preferably Compound A) for the treatment of novel hormonal agent (NHA)-naive prostate cancer.In some embodiments, the subject has undergone two previous chemotherapy regimens.In some embodiments, the subject has undergone one previous chemotherapy regimen.In some embodiments, the subject has not undergone any previous chemotherapy regimen.

[0504] In some embodiments, the subject has an ECOG performance status of 0 or 1. In some embodiments, the subject has an ECOG performance status of 1. In some embodiments, the subject has an ECOG performance status of 0.

[0505] In some embodiments, the subject does not have symptomatic brain metastases requiring greater than physiological replacement doses of steroids.

[0506] In some embodiments, the subject does not have active inflammatory bowel disease.

[0507] In some embodiments, the subject does not have chronic diarrhea.

[0508] In some embodiments, the subject does not have diverticular disease.

[0509] In some embodiments, the subject has not previously undergone gastrectomy.

[0510] In some embodiments, the subject has not previously undergone lap-band surgery.

[0511] In some embodiments, the subject has not undergone prior radiation therapy within four weeks prior to the first administration of a compound of the present disclosure.

[0512] In some embodiments, the subject has not previously undergone radiation therapy that irradiates more than about 25% of the patient's bone marrow.

[0513] In some embodiments, the subject has not received an investigational drug within four weeks prior to the first administration of a compound of the present disclosure.

[0514] In some embodiments, the subject has not received systemic anti-cancer therapy within two weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure. In some embodiments, the subject has not received systemic anti-cancer therapy, other than an agent to maintain castration, within two weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure.

[0515] In some embodiments, the subject has not received bicalutamide within 6 weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure.

[0516] In some embodiments, the subject has not received mitomycin C within 6 weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure.

[0517] In some embodiments, the subject has not received a nitrosourea within 6 weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure.

[0518] In some embodiments, the subject has not received abiraterone or abiraterone acetate within 4 weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure.

[0519] In some embodiments, subjects with prostate cancer (e.g., mCRPC) respond differently to treatment with a compound of the present disclosure (preferably Compound A) or a pharmaceutically acceptable salt thereof depending on the subject's AR biomarker status, i.e., whether the subject has one or more somatic tumor mutations to AR.

[0520] In some embodiments, the prostate cancer subject comprises at least one somatic AR tumor mutation.

[0521] In some embodiments, the prostate cancer subject comprises a somatic AR tumor mutation of at least L702.

[0522] In some embodiments, the prostate cancer subject comprises at least the L702H somatic AR tumor mutation.

[0523] In some embodiments, the prostate cancer subject comprises at least the M895 somatic AR tumor mutation.

[0524] In some embodiments, the prostate cancer subject comprises at least the M895V somatic AR tumor mutation.

[0525] In some embodiments, the prostate cancer subject comprises a somatic AR tumor mutation of at least W742.

[0526] In some embodiments, the prostate cancer subject comprises at least the W742C somatic AR tumor mutation.

[0527] In some embodiments, the prostate cancer subject comprises a somatic AR tumor mutation of at least S889.

[0528] In some embodiments, the prostate cancer subject comprises at least the S889G somatic AR tumor mutation.

[0529] In some embodiments, the prostate cancer subject comprises at least an M750 somatic AR tumor mutation.

[0530] In some embodiments, the prostate cancer subject comprises at least the M750V somatic AR tumor mutation.

[0531] In some embodiments, the prostate cancer subject comprises at least the M896 somatic AR tumor mutation.

[0532] In some embodiments, the prostate cancer subject comprises at least the M896V somatic AR tumor mutation.

[0533] In some embodiments, the prostate cancer subject comprises at least the T878 somatic AR tumor mutation.

[0534] In some embodiments, the prostate cancer subject comprises at least the T878A somatic AR tumor mutation.

[0535] In some embodiments, the prostate cancer subject comprises at least the T878S somatic AR tumor mutation.

[0536] In some embodiments, the prostate cancer subject comprises at least the F877 somatic AR tumor mutation.

[0537] In some embodiments, the prostate cancer subject comprises at least the F877L somatic AR tumor mutation.

[0538] In some embodiments, the prostate cancer subject comprises at least the D891 somatic AR tumor mutation.

[0539] In some embodiments, the prostate cancer subject comprises at least the D891H somatic AR tumor mutation.

[0540] In some embodiments, the prostate cancer subject comprises at least the H875 somatic AR tumor mutation.

[0541] In some embodiments, the prostate cancer subject comprises at least the H875Y somatic AR tumor mutation.

[0542] In some embodiments, the prostate cancer subject comprises at least two somatic AR tumor mutations.

[0543] In some embodiments, the prostate cancer subject comprises at least two somatic AR tumor mutations: T878A / D891H.

[0544] In some embodiments, the prostate cancer subject contains at least two somatic AR tumor mutations: T878A / S889G.

[0545] In some embodiments, the prostate cancer subject comprises at least two somatic AR tumor mutations, F877L / T878A.

[0546] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations: L702H and T878A.

[0547] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations: L702H and T878A.

[0548] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations: L702H and T878S.

[0549] In some embodiments, the prostate cancer subject comprises two somatic AR tumor mutations: L702H and T878S.

[0550] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, L702H and H875Y.

[0551] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations: L702H and H875Y.

[0552] In some embodiments, the subject with prostate cancer has at least two somatic AR tumor mutations: T878A and H875Y.

[0553] In some embodiments, the prostate cancer subject comprises two somatic AR tumor mutations: T878A and H875Y.

[0554] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations: T878S and H875Y.

[0555] In some embodiments, the prostate cancer subject comprises two somatic AR tumor mutations: T878S and H875Y.

[0556] In some embodiments, the subject with prostate cancer comprises at least three somatic AR tumor mutations: L702H, T878A, and H875Y.

[0557] In some embodiments, the prostate cancer subject comprises three somatic AR tumor mutations: L702H, T878A, and H875Y.

[0558] In some embodiments, the prostate cancer subject comprises at least three somatic AR tumor mutations: L702H, T878S, and H875Y.

[0559] In some embodiments, the prostate cancer subject comprises three somatic AR tumor mutations: L702H, T878S, and H875Y.

[0560] In some embodiments, the prostate cancer subject comprises at least one somatic AR tumor mutation that is not L702H, T878A, T878S, or H875Y.

[0561] In some embodiments, the prostate cancer subject comprises one somatic AR tumor mutation that is not L702H, T878A, T878S, or H875Y.

[0562] In some embodiments, the prostate cancer subject comprises at least two somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0563] In some embodiments, the prostate cancer subject comprises two somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0564] In some embodiments, the subject with prostate cancer comprises at least three somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0565] In some embodiments, the subject has prostate cancer with three somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0566] In one aspect, the present application relates to treating prostate cancer using a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is prostate adenocarcinoma. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castrate-resistant or castration-resistant prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is advanced mCRPC. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castrate-sensitive or castration-sensitive prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-sensitive prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is novel hormonal agent (NHA)-naive prostate cancer. In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is novel hormonal agent (NHA)-naive metastatic prostate cancer.In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs). In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs). In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs). In some embodiments, the prostate cancer treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs). In some embodiments, the additional anticancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, zoledronic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional anticancer agent is abiraterone or a pharmaceutically acceptable salt thereof. In some embodiments, the additional anticancer agent is abiraterone acetate or a pharmaceutically acceptable salt thereof. In some embodiments, the additional anticancer agent is abiraterone acetate.

[0567] In some embodiments, the present application relates to treating prostate cancer using a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent, wherein the subject has not previously been administered a novel hormonal agent (NHA). In some embodiments, the NHA is an androgen biosynthesis inhibitor. In some embodiments, the NHA is an androgen receptor blocker. In some embodiments, the NHA is abiraterone. In some embodiments, the NHA is abiraterone acetate. In some embodiments, the NHA is enzalutamide. In some embodiments, the NHA is darolutamide. In some embodiments, the NHA is apalutamide.

[0568] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is prostate adenocarcinoma.

[0569] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic prostate cancer.

[0570] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castrate-resistant or castration-resistant prostate cancer.

[0571] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-resistant prostate cancer.

[0572] In some embodiments, the subject has not previously received a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is advanced mCRPC.

[0573] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is castrate-sensitive or castration-sensitive prostate cancer.

[0574] In some embodiments, the subject has not previously been administered a novel hormonal agent (NHA), and the prostate cancer being treated with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof) in combination with another anti-cancer agent is metastatic castration-sensitive prostate cancer.

[0575] In some embodiments, the additional anticancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, zoledronic acid, or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the additional anticancer agent is abiraterone or a pharmaceutically acceptable salt thereof.

[0577] In some embodiments, the additional anticancer agent is abiraterone acetate or a pharmaceutically acceptable salt thereof.

[0578] In some embodiments, the additional anticancer agent is abiraterone acetate.

[0579] In one embodiment, cancer treatment reduces tumor size. A reduction in tumor size can also be referred to as "tumor regression." Preferably, the tumor size after treatment is reduced by 5% or more compared to the tumor size before treatment, more preferably, the tumor size is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by more than 75% or more. Tumor size can be measured by any reproducible measurement means. In a preferred embodiment, tumor size can be measured as tumor diameter.

[0580] In another embodiment, treating cancer results in a reduction in tumor volume. Preferably, the tumor volume after treatment is reduced by 5% or more compared to the tumor volume before treatment, more preferably by 10% or more, more preferably by 20% or more, more preferably by 30% or more, more preferably by 40% or more, even more preferably by 50% or more, and most preferably by more than 75% or more. Tumor volume can be measured by any reproducible means of measurement.

[0581] In another aspect, treating cancer reduces tumor count. Preferably, the tumor count after treatment is reduced by 5% or more compared to the tumor count before treatment, more preferably by 10% or more, more preferably by 20% or more, more preferably by 30% or more, more preferably by 40% or more, even more preferably by 50% or more, and most preferably by more than 75%. The tumor count can be measured by any reproducible measurement means. In a preferred aspect, the tumor count can be measured by counting tumors visible to the naked eye or under a specific magnification. In a preferred aspect, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0582] In another aspect, treating cancer reduces the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, the number of metastatic lesions after treatment is reduced by 5% or more compared to the number before treatment, more preferably by 10% or more, more preferably by 20% or more, more preferably by 30% or more, more preferably by 40% or more, even more preferably by 50% or more, and most preferably by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement means. In a preferred aspect, the number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or under a specific magnification. In a preferred aspect, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0583] In another embodiment, treating cancer increases the mean survival time of a population of treated subjects compared to a population administered 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 mean survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in mean survival time of a population can be measured, for example, by calculating the mean survival time of the population after initiation of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in mean survival time of a population can also be measured, for example, by calculating the mean survival time of the population after completion of the first round of treatment with an active agent or compound of the present disclosure.

[0584] In another embodiment, treating cancer increases the mean survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the mean survival time is increased by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in mean survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in mean survival time of a population can be measured by calculating the mean survival time of the population after initiation of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in mean survival time of a population can be measured by calculating the mean survival time of the population after completion of the first treatment with a compound of the present disclosure (preferably Compound A or a pharmaceutically acceptable salt thereof).

[0585] In another embodiment, treating cancer reduces tumor growth rate. Preferably, tumor growth rate after treatment is reduced by at least 5% compared to the growth rate before treatment, more preferably, tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%. Tumor growth rate can be measured by any reproducible means of measurement. In a preferred embodiment, tumor growth rate is measured by the change in tumor diameter per unit time.

[0586] In another embodiment, treating cancer reduces tumor regrowth. Preferably, tumor regrowth after treatment 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 can be measured by any reproducible means of measurement. In a preferred embodiment, tumor regrowth is measured by measuring the increase in tumor diameter from a previous tumor shrinkage after treatment. In another preferred embodiment, reduced tumor regrowth is indicated by failure of tumor to recur after termination of treatment.

[0587] In some embodiments, the subject is also administered a gastric acid modifier, a PPI, or an H2 compound. In some embodiments, the subject initiates, continues, or maintains the same level of treatment with a gastric acid modifier while being treated with a compound of Formula (I) (e.g., Compound A).

[0588] In some embodiments, a subject should not initiate, continue, or maintain the same level of treatment with a gastric acid modifier while being treated with a compound of Formula (I) (e.g., Compound A). In some embodiments, the gastric acid modifier is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid modifier is an H2 compound. In some embodiments, the gastric acid modifier is an antacid.

[0589] In some embodiments, the subject should discontinue treatment with or use of a gastric acid modifying drug from a time point before initiating administration of a compound of Formula (I) (e.g., Compound A). In some embodiments, the time point is at least 1 hour. In some embodiments, the time point is at least 2 hours. In some embodiments, the time point is at least 3 hours. In some embodiments, the time point is at least 4 hours. In some embodiments, the time point is at least 5 hours. In some embodiments, the time point is at least 6 hours. In some embodiments, the time point is at least 7 hours. In some embodiments, the time point is at least 8 hours. In some embodiments, the time point is at least 9 hours. In some embodiments, the time point is at least 10 hours. In some embodiments, the time point is at least 11 hours. In some embodiments, the time point is at least 12 hours. In some embodiments, the time point is at least 24 hours. In some embodiments, the time point is at least 36 hours. In some embodiments, the time point is at least 48 hours. In some embodiments, the time point is at least 60 hours. In some embodiments, the time point is at least 72 hours. In some embodiments, the gastric acid modifier is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid modifier is an H2 compound. In some embodiments, the gastric acid modifier is an antacid.

[0590] In some embodiments, the subject should reduce the level of treatment or use of a gastric acid modifying drug from a time point before initiating administration of a compound of Formula (I) (e.g., Compound A). In some embodiments, the time point is at least 1 hour. In some embodiments, the time point is at least 2 hours. In some embodiments, the time point is at least 3 hours. In some embodiments, the time point is at least 4 hours. In some embodiments, the time point is at least 5 hours. In some embodiments, the time point is at least 6 hours. In some embodiments, the time point is at least 7 hours. In some embodiments, the time point is at least 8 hours. In some embodiments, the time point is at least 9 hours. In some embodiments, the time point is at least 10 hours. In some embodiments, the time point is at least 11 hours. In some embodiments, the time point is at least 12 hours. In some embodiments, the time point is at least 24 hours. In some embodiments, the time point is at least 36 hours. In some embodiments, the time point is at least 48 hours. In some embodiments, the time point is at least 60 hours. In some embodiments, the time point is at least 72 hours. In some embodiments, the gastric acid modifier is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid modifier is an H2 compound. In some embodiments, the gastric acid modifier is an antacid.

[0591] In some embodiments, a subject should not initiate, continue, or maintain the same level of treatment with a PPI or H2 compound while being treated with a compound of Formula (I) (e.g., Compound A). In some embodiments, the PPI is esomeprazole.

[0592] In some embodiments, a subject should not initiate, continue, or maintain the same level of treatment with a PPI while being treated with a compound of Formula (I) (e.g., Compound A). In some embodiments, the PPI is esomeprazole.

[0593] In some embodiments, a subject should not initiate, continue, or maintain the same level of treatment with esomeprazole while being treated with Compound A.

[0594] In some embodiments, the present invention provides a packaged dosage form of a compound of Formula (I) (e.g., Compound A) with printed instructions to avoid, reduce, or discontinue administration or use of a PPI or an H2 compound prior to administration or use of a compound of Formula (I) (e.g., Compound A). In some embodiments, the PPI is esomeprazole.

[0595] In some embodiments, the present invention provides a packaged dosage form of Compound A with printed instructions to avoid, reduce, or discontinue administration or use of a PPI prior to administration or use of Compound A. In some embodiments, the PPI is esomeprazole.

[0596] A positive effect of food has been observed in humans receiving or using Compound A. For example, consuming a high-fat meal before administration or use of Compound A reduces the observed C of Compound A compared to humans who do not consume a high-fat meal before administration or use of Compound A. max There was a significant increase in the level of systemic exposure by about 4-fold and by about 3-fold. In some embodiments, Compound A is administered or used orally with food, i.e., the subject is in a fed state.

[0597] In some embodiments, the combined use of PPIs and Compound A should be avoided.

[0598] In some embodiments, if treatment with or use of a PPI is indicated and no alternative is available, Compound A is administered or used orally with food, i.e., it is recommended that the subject be in a fed state, for example, by consuming a moderate-fat meal (400-800 calories, approximately 35% fat), before Compound A is administered or used.

[0599] In some embodiments, an H2 blocker (e.g., cimetidine, famotidine) or a topical antacid (e.g., aluminum hydroxide, calcium carbonate, bismuth subsalicylate) may be used. In some embodiments, Compound A is administered or used at least 2 hours before or 10-12 hours after the administration or use of the H2 blocker. In some embodiments, Compound A is administered or used at least 2 hours before or after the administration or use of the antacid.

[0600] The dosage of the compounds of the present disclosure for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the treating clinician or physician, among other factors that will affect the selected dosage.

[0601] The therapeutically effective amount of the compound of the present disclosure can be administered once or more times a day for up to 30 days or more, followed by one or more days without administering the compound.This type of treatment regimen, that is, daily administration of the compound of the present disclosure followed by daily non-administration of the compound, can be called a treatment cycle.The treatment cycle can be repeated as many times as necessary to achieve the intended effect.

[0602] In some embodiments, the therapeutically effective amount of a compound of the disclosure 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, 5 40, 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, 69 5, 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, taken once, twice, three times, four times, or or more for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 consecutive days, or once, twice, three, four or more times daily, in single or divided doses, for 2, 3, 4, 5, 6 or more months.

[0603] In some embodiments, a therapeutically effective amount of a compound of the present disclosure 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 240 to about 250 mg, about 260 to about 270 mg, about 280 to about 290 mg, about 300 to about 310 mg, about 320 to about 330 mg, about 340 to about 350 mg, about 360 to about 370 mg, about 380 to about 390 mg, about 400 to about 410 mg, about 420 to about 430 mg, about 440 to about 450 mg, about 460 to about 470 mg, about 480 to about 490 mg, about 490 to about 500 mg, about 510 to about 520 mg, about 530 to about 540 mg, about 550 to about 560 mg, about 570 to about 580 mg, about 590 to about 600 mg, about 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 440mg, about 420 to about 450mg, about 430 to about 460mg, about 440 to about 470mg, about 450 to about 480mg, about 460 to about 490mg, about 470 to about 500mg, about 480 to about 510mg, about 490 to about 520mg, about 500 to about 530mg, about 510 to about 540mg, about 520 to about 550mg, about 530 to about 560mg, about 540 to about 570mg, about 550 to about 580mg, about 560 to about 590mg, about 570 to about 600mg, about 580 to about 610mg, about 590 to about 620mg, about 600 to about 630mg, about 610 to about 640mg, about 62 0~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~710mg, 690~720mg, 700~730mg, 710~740mg, 720~7 50 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,The dose is 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, and may be administered once, twice, three times, four or more times daily in a single dose or in divided doses (the dose depends on the patient's body weight (kg), body surface area (m), 2 ), and / or may be adjusted according to age.

[0604] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is from about 5 mg to about 250 mg.

[0605] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is from about 250 mg to about 500 mg.

[0606] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is from about 500 mg to about 750 mg.

[0607] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is from about 70 mg to about 1000 mg, administered once, twice, three times, four times or more daily in a single dose or in divided doses (dosage is based on patient weight (kg), body surface area (m 2 ), and / or may be adjusted according to age.

[0608] In some embodiments, the therapeutically effective amount of a compound of the disclosure is about 70 mg, 105 mg, 140 mg, 175 mg, 210 mg, 245 mg, 280 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg, or 700 mg administered once, twice, three times, four or more times daily in a single dose or in divided doses (dosage is based on the patient's weight (kg), body surface area (m) 2 ), and / or may be adjusted according to age).

[0609] In some embodiments, the therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

[0610] In some embodiments, the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0611]

[0609]

[0612] In some embodiments, the therapeutically effective amount of Compound A is from about 10 mg to about 500 mg.

[0613] In some embodiments, the therapeutically effective amount of Compound A is from about 20 mg to about 250 mg.

[0614] In some embodiments, the therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0615] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 100 mg, about 150 mg, or about 300 mg.

[0616] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 100 mg.

[0617] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 100 mg.

[0618] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 100 mg administered orally once daily.

[0619] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 150 mg.

[0620] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 150 mg.

[0621] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 150 mg administered orally once daily.

[0622] In some embodiments, the therapeutically effective amount of Compound A is about 200 mg.

[0623] In some embodiments, the therapeutically effective amount of Compound A is 200 mg.

[0624] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 150 mg administered orally once daily.

[0625] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 300 mg.

[0626] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 300 mg.

[0627] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 300 mg administered orally once daily.

[0628] In some embodiments, the therapeutically effective amount of Compound A is about 320 mg.

[0629] In some embodiments, the therapeutically effective amount of Compound A is 320 mg.

[0630] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 320 mg administered orally once daily.

[0631] In some embodiments, the therapeutically effective amount of Compound A is about 400 mg.

[0632] In some embodiments, the therapeutically effective amount of Compound A is 400 mg.

[0633] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 400 mg administered orally once daily.

[0634] In some embodiments, the therapeutically effective amount of Compound A is about 480 mg.

[0635] In some embodiments, the therapeutically effective amount of Compound A is 480 mg.

[0636] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 480 mg administered orally once daily.

[0637] In some embodiments, the therapeutically effective amount of Compound A is about 500 mg.

[0638] In some embodiments, the therapeutically effective amount of Compound A is 500 mg.

[0639] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is 500 mg administered orally once daily.

[0640] A therapeutically effective amount of a compound of the present disclosure may also range from about 0.01 mg / kg per day to about 100 mg / kg per day. In some embodiments, a therapeutically effective amount of a compound of the present disclosure may range from about 0.05 mg / kg per day to about 10 mg / kg per day. In some embodiments, a therapeutically effective amount of a compound of the present disclosure may range from about 0.075 mg / kg per day to about 5 mg / kg per day. In some embodiments, a therapeutically effective amount of a compound of the present disclosure may range from about 0.10 mg / kg per day to about 1 mg / kg per day. In some embodiments, a therapeutically effective amount of a compound of the present disclosure may range from about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0641] In some embodiments, the therapeutically effective amount of a compound of the present disclosure 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.

[0642] In some embodiments, a therapeutically effective amount of a compound of the present disclosure 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, about 1.95 mg / kg per day, about 1.95 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 1.95 mg / kg per day, about 1.15 mg / kg per day, about 1.16 mg / kg per day, about 1.17 mg / kg per day, about 1.18 mg / kg per day, about 1.19 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 about 1.50 mg / kg, 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.

[0643] In some embodiments, the therapeutically effective amount of a compound of the present disclosure 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.

[0644] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is administered to a subject once daily. In some embodiments, the daily dose of a compound of the present disclosure may be administered all at once to a subject. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in two separate doses (i.e., split doses). In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in three separate doses. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in four separate doses. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in five or more separate doses. In some embodiments, these partial or split doses are administered to a subject at regular intervals throughout the day, such as every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0645] Therapeutically effective amounts of compounds of the present disclosure can be estimated initially either in cell culture assays or animal models (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50(the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0646] Dosage and administration are adjusted to provide sufficient levels of the disclosed compounds or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, once every two weeks, or monthly, depending on the half-life and clearance rate of the particular formulation.

[0647] In some embodiments, with respect to the method of treating prostate cancer with a combination of a compound of the present disclosure and another anti-cancer agent, a therapeutically effective amount of a compound of the present disclosure is described herein, and the therapeutically effective amount of the anti-cancer 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, 0, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 1 50, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 3 05, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 46 0, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615 , 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 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 administered once, twice, three, four or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 30 consecutive days, or once, twice, three, four or more times daily, in single or divided doses, for 2, 3, 4, 5, 6, or more months.

[0648] In some embodiments, for methods of treating prostate cancer with a combination of a compound of the present disclosure and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate, a therapeutically effective amount of a compound of the present disclosure is described herein, and the therapeutically effective amount of abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 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 ,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 3, 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, 1 60, 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, 31 5, 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 administered once, twice, three, four or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 30 consecutive days, or once, twice, three, four or more times daily, in single or divided doses, for 2, 3, 4, 5, 6, or more months. In some embodiments, for methods of treating prostate cancer with a combination of a compound of the disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of a compound of the disclosure is described herein, wherein the therapeutically effective amount of abiraterone acetate is about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,250 mg, or about 1,500 mg administered once daily.

[0649] In some embodiments, with respect to the method of treating prostate cancer with a combination of a compound of the disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of the compound of the disclosure is described herein, wherein the therapeutically effective amount of abiraterone acetate is about 125 mg, about 250 mg, about 375 mg, about 500 mg, about 625 mg, about 750 mg, about 875 mg, about 1,000 mg, about 1,125 mg, about 1,250 mg, about 1,375 mg, or about 1,500 mg administered once daily.

[0650] In some embodiments, with respect to the method of treating prostate cancer with a combination of a compound of the disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of the compound of the disclosure is described herein, wherein the therapeutically effective amount of abiraterone acetate is about 125 mg, about 250 mg, about 375 mg, about 500 mg, about 625 mg, about 750 mg, about 875 mg, about 1,000 mg, about 1,125 mg, about 1,250 mg, about 1,375 mg, or about 1,500 mg administered twice daily.

[0651] In some embodiments, with respect to the method of treating prostate cancer with a combination of a compound of the disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of the compound of the disclosure is described herein, wherein the therapeutically effective amount of abiraterone acetate is about 125 mg, about 250 mg, about 375 mg, about 500 mg, about 625 mg, about 750 mg, about 875 mg, about 1,000 mg, about 1,125 mg, about 1,250 mg, about 1,375 mg, or about 1,500 mg administered three times daily.

[0652] In some embodiments, for the method of treating prostate cancer with a combination of a compound of the present disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of a compound of the present disclosure (preferably Compound A) is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg administered orally once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30, or more days in a single or divided dose. In some embodiments, the abiraterone acetate is administered in combination with a corticosteroid and administered orally once or twice daily. In some embodiments, the abiraterone acetate is administered in combination with 5 mg of prednisone or prednisolone and administered orally twice daily.

[0653] In some embodiments, for the method of treating prostate cancer with a combination of a compound of the present disclosure (preferably Compound A) and abiraterone acetate, a therapeutically effective amount of a compound of the present disclosure (preferably Compound A) is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg administered orally once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, or more days in a single or divided dose. In some embodiments, the abiraterone acetate is administered in combination with 5 mg of prednisone and administered orally twice daily. In some embodiments, the combination of a compound of the present disclosure (preferably Compound A) and abiraterone acetate is administered to a subject in need thereof in the fasted state. In some embodiments, the subject fasts for at least 2 hours before and at least 1 hour after administration of the combination of a compound of the disclosure (preferably Compound A) and abiraterone acetate.

[0654] In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone acetate are administered to the subject simultaneously. In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone acetate are administered to the subject sequentially.

[0655] In some embodiments, a compound of the present disclosure (preferably Compound A) and the anti-cancer agent are administered to the subject in close temporal proximity.

[0656] In some embodiments, "temporal proximity" means that the administration of a compound of the present disclosure occurs within a period before or after the administration of an anti-cancer agent, such that the therapeutic effect of the compound of the present disclosure overlaps with the therapeutic effect of the anti-cancer agent. In some embodiments, the therapeutic effect of a compound of the present disclosure completely overlaps with the therapeutic effect of the anti-cancer agent. In some embodiments, "temporal proximity" means that the administration of a compound of the present disclosure occurs within a period before or after the administration of an anti-cancer agent, such that a synergistic effect exists between the compound of the present disclosure and the anti-cancer agent. In some embodiments, the anti-cancer agent is abiraterone acetate.

[0657] "Proximity in time" can vary depending on various factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route(s) by which the therapeutic agent is administered. In some embodiments, "proximity in time" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be administered in close temporal proximity to a single administration of another therapeutic agent. In some embodiments, the temporal proximity may vary during a treatment cycle or dosing regimen.

[0658] In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are administered to the subject simultaneously.

[0659] In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are administered to the subject simultaneously in separate formulations (e.g., separate tablets). In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are administered to the subject simultaneously in the same formulation (e.g., a single tablet).

[0660] In some embodiments, a compound of the disclosure (preferably Compound A) and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are administered sequentially to the subject.

[0661] In some embodiments, a compound of the present disclosure (preferably Compound A) and abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are administered closely in time to the subject.

[0662] In some embodiments, a compound of the present disclosure (preferably Compound A) is administered to the subject before abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate is administered to the subject, and the subject is in a fasted state.

[0663] In some embodiments, a compound of the present disclosure (preferably Compound A) is administered to the subject before abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate is administered to the subject, and the subject is in a fed state.

[0664] In some embodiments, a compound of the present disclosure (preferably Compound A) is administered to the subject after abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate has been administered to the subject, and the subject is in a fasted state.

[0665] In some embodiments, a compound of the present disclosure (preferably Compound A) is administered to the subject after abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate has been administered to the subject, and the subject is in a fed state.

[0666] Pharmaceutical Composition In some embodiments, the compound of the present disclosure (preferably Compound A) is formulated for oral administration. For example, in some embodiments, the compound of the present disclosure (preferably Compound A) is formulated as a tablet containing 0, 1, 2, or more of each of an emulsifier, a surfactant, a binder; a disintegrant, a glidant; and a lubricant.

[0667] In some embodiments, the emulsifier is hypromellose.

[0668] In some embodiments, the surfactant is vitamin E polyethylene glycol succinate.

[0669] In some embodiments, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0670] In some embodiments, the disintegrant is croscarmellose sodium.

[0671] In some embodiments, the glidant refers to a substance used to promote powder flow by reducing interparticle cohesion. In some embodiments, in the dosage forms of the present disclosure, the glidant is selected from the group consisting of silicon dioxide, colloidal anhydrous silica, starch, and talc.

[0672] In some embodiments, the lubricant refers to a substance that prevents ingredients from sticking and / or clumping in machinery used to prepare the dosage forms of the present disclosure. In some embodiments, 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.

[0673] Pharmaceutical compositions containing the compound of the present disclosure (preferably Compound A) can be prepared by a generally known method, for example, by conventional mixing, dissolving, granulating, sugar-coating, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the compound of the present disclosure into a pharmaceutically usable preparation. Naturally, the appropriate formulation depends on the selected route of administration.

[0674] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved 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, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, 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 isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0675] Sterile injectable solutions can be prepared by incorporating the required amount of the compound of the present disclosure (preferably Compound A) into a suitable solvent with one or a combination of the above-mentioned components as needed, followed by filtration sterilization.Generally, dispersions are prepared by incorporating the active agent or compound into a sterile medium, which contains a basic dispersion medium and other required components from those mentioned above.For sterile powders for preparing sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which allows the powder of the active ingredient and any desired additional ingredients to be obtained from the solution previously sterile-filtered.

[0676] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds of the present disclosure may be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a liquid carrier used as a mouthwash, in which the drug or compound in the liquid carrier is orally administered, swished in the mouth, expectorated, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0677] For administration by inhalation, the agents or compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0678] Systemic administration may be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved using nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into an ointment, salve, gel, or cream that is generally known in the art.

[0679] In one embodiment, the compound of the present disclosure (preferably Compound A) is prepared with a pharmaceutically acceptable carrier that protects the drug or compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, 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. Such materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells containing monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, the methods described in U.S. Pat. No. 4,522,811.

[0680] 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 a physically discrete unit suitable for unitary administration to the subject to be treated, each unit containing a predetermined amount of active agent or compound calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier.The specification of the unit dosage form of the present application is determined by and directly depends on the inherent characteristics of the compound of the present disclosure and the specific therapeutic effect to be achieved.

[0681] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0682] Exemplary administration methods for the compounds of the present disclosure (preferably Compound A) include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration. In some embodiments, the compounds of the present disclosure are administered orally. In some embodiments, the compounds of the present disclosure are administered as tablets, capsules, caplets, liquids, suspensions, syrups, granules, beads, powders, or pellets.

[0683] An exemplary pharmaceutical composition includes a salt of a compound of the present disclosure (preferably Compound A) and a pharmaceutically acceptable carrier, such as: a) a diluent, such as purified water, triglyceride oil, e.g., hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, e.g., EPA or DHA, or esters thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, for example glucose or beta-lactose, corn sweeteners, natural and synthetic gums, for example acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone (optionally); d) disintegrating agents, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersing agents, for example Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, peceol, transquitol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier, and / or an agent that improves absorption of g) salts, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200.

[0684] Inert pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of the present disclosure, or their salts or hydrates, can be either solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be comprised of about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules may be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for manufacturing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0685] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid preparations may also include solutions for nasal administration.

[0686] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc., for example, by dissolving or mixing a salt of the present disclosure in a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the compounds of the present disclosure.

[0687] Parenteral injectable administration is typically used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0688] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, eg nitrogen.

[0689] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0690] Depending on the intended method of administration, the compositions of the present disclosure may be in solid, semi-solid, or liquid dosage forms, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice, such as injectables, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, etc. Likewise, the compositions may also be administered in intravenous (both bolus and infusion), intraperitoneal, intrathecal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0691] The pharmaceutical compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the free base or salt of the present disclosure by weight or volume.

[0692] Pharmaceutical compositions comprising a compound of the present disclosure (preferably Compound A) may further comprise one or more additional anti-cancer agents, including any of those disclosed herein.

[0693] All amounts of any component of the oral dosage forms, e.g., tablets, described herein given on a w / w % basis refer to the total weight of the oral dosage form unless otherwise specified. [Example]

[0694] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are not intended to limit the scope of the disclosure. It should also be understood that various other embodiments, modifications thereof, and equivalents thereof that may be suggested to those skilled in the art may be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0695] Example 1 - Degradation of AR in Wild-Type LNCaP and VCaP Cells

[0696] To identify the in vitro pharmacological effects of Compound A, an AR degradation assay was performed in VCaP (vertebrate-prostate cancer) and LNCaP (lymph node prostate cancer) cancer cells, which harbor AR amplification and AR mutation (T878A), respectively (Figure 2). After 24 hours of treatment, Compound A effectively degraded AR in LNCaP (D max ≥91% DC 50 ≦1.3 nM) and VCaP (D max ≥94% DC 50 Compound A was degraded at low concentrations (<1 nM). Similar degradation time-course experiments in VCaP cells demonstrated that greater than 50% AR degradation was achieved within 2 hours of treatment with Compound A, and that by 6 hours, AR was nearly completely lost from the cells. Compound A is believed to engage the cereblon protein at the same binding site as immunomodulatory imid drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide; therefore, excess pomalidomide competes for Compound A binding to the cereblon protein. Consistent with a PROTAC mechanism of action, pomalidomide (10 μM) blocked Compound A-mediated degradation. Furthermore, polyubiquitination assays demonstrated that AR ubiquitination was significantly increased by Compound A treatment. These data support the proposed mechanism of action of Compound A in degrading AR through engagement of the E3 ligase cereblon, AR ubiquitination, and proteasome-mediated degradation.

[0697] Example 2 - Degradation of AR proteins with clinically relevant point mutations

[0698] To evaluate the ability of Compound A to degrade AR variants, vectors expressing wild-type or mutant AR proteins with clinically observed mutations in the ligand-binding domain (13 with a single amino acid change and 4 with two amino acid changes) were used (Azad AA, Volik SV, Wyatt AW, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315-2324; Robinson D., Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215-1228; Ledet EM, Lilly MB, Sonpavde G., et al. Comprehensive analysis of AR alterations in circulating tumor DNA from patients with advanced prostate cancer. Oncologist. 2020 Apr;25(4):327-333) was stably transfected into HEK293 or T-REx™-293 cells, which do not express endogenous AR (Table 1, Figure 3, and Figure 10). Compound A-mediated degradation of all clinically relevant AR point mutants tested was comparable to that observed with wild-type AR.

[0699] [Table 2]

[0700] Example 3 - In vitro evaluation of the neosubstrate degrading potential of cereblon

[0701] Treatment of Ramos and SK-N-DZ cells with 1 μM Compound A did not result in degradation of GSPT1, Aiolos, Ikaros, CK1α, or SALL4 (Figure 4). Other PROTAC control compounds (Con A-D), A3370 (a known neosubstrate degrader), and 10 mM lenalidomide were also tested. Compound A engages the cereblon protein at the same site as IMiDs. Lenalidomide and A3370 induced the degradation of CBN neosubstrates, as expected. Because Compound A does not cause degradation of known cereblon neosubstrates, potential obstacles attributed to the IMiD class (thalidomide, pomalidomide, and lenalidomide) may not apply to Compound A.

[0702] Example 4 - Inhibition of prostate tumor growth by Compound A in the VCaP model in intact (non-castrated) mice

[0703] To mimic the high androgen levels found in an incompletely testosterone-suppressed environment, intact (non-castrated) mice were used in VCaP tumor xenograft studies. Published data for enzalutamide have shown very modest or no activity in the intact VCaP setting (Asangani, IA, Dommeti, VL, Wang, X., et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278-282; Li, J., Alyamani, M., Zhang, A., et al. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide-resistant prostate cancer. Elife. 2017;6,17 pages). Mice were treated orally once daily (QD) with vehicle, enzalutamide (20 mg / kg, "ENZA"), or Compound A (10, 3, and 1 mg / kg / day) for 21 days. As shown in Figure 5, Compound A at 10, 3, and 1 mg / kg / day demonstrated tumor growth inhibition (TGI) of 98%, 74%, and 34%, respectively, while limited efficacy was observed in mice treated with enzalutamide (TGI = 27%).

[0704] Plasma PSA levels are used as a clinical biomarker of disease progression and are thought to be closely related to the degree of AR activity (Catalona, ​​WJ, Richie, JP, Ahmann, FR, et al. Comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. The Journal of Urology. 1994;151(5):1283-1290; Cleutjens, KB, van Eekelen, CC, van der Korput, HA, et al. Two androgen response regions cooperate in steroid hormone-regulated activity of the prostate-specific antigen promoter. J Biol Chem. 1996;271(11):6379-6388). Plasma PSA levels after Compound A treatment were assessed by ELISA in samples from intact VCaP tumor models. As shown in Figure 6, all three doses of Compound A dose-dependently reduced PSA levels in tumor-bearing mice. In particular, Compound A at 3 mg / kg and 10 mg / kg reduced PSA levels more potently than enzalutamide at 20 mg / kg. Consistently, the level of PSA reduction by Compound A correlates with the TGI shown in Figure 5.

[0705] These TGI and PSA data further demonstrate that Compound A inhibits AR signaling in the presence of high concentrations of androgen.

[0706] Example 5 - Effect of Compound A on food / proton pump inhibitor (PPI) in healthy volunteer subjects.

[0707] Healthy volunteers were given a single oral dose of Compound A in both fasted and fed states, and co-administered with the PPI esomeprazole in the fed state. The primary endpoint was AUC inf and C max Further parameters measured were AUC last and T max A single oral dose of Compound A was generally well tolerated in healthy male participants, with no meaningful differences in the safety profile whether administered in the fasted or fed state or in combination with esomeprazole.

[0708] Primary PK parameters showed less variability in the fed state compared with the fasted state. Food prolonged absorption and significantly increased peak concentrations and the extent of systemic exposure of Compound A.

[0709] Similar variability was observed between administration of Compound A alone and co-administration of Compound A with esomeprazole. Co-administration slightly reduced peak concentrations and the extent of systemic exposure of Compound A.

[0710] This Phase 1, open-label study included a crossover, fed / fasted cohort, and fixed-sequence PPI cohort. In the fed / fasted cohort, healthy male volunteers received a single oral dose of Compound A 200 mg in the fasted state (Treatment A) and in the fed state after a high-calorie / high-fat meal (Treatment B). Participants were randomized to the administration sequence of Treatments AB or BA. In the PPI cohort, participants received only a single oral dose of Compound A 300 mg in the fed state (Treatment C). In Treatment D, participants received esomeprazole 40 mg for 5 days in the fed state followed by a single oral dose of Compound A 300 mg on the 5th day. Participants were assigned to a fixed administration sequence of Treatments CD. A 24-day washout period was allowed between doses of Compound A. PK blood samples were collected pre-dose and at selected time points up to 312 hours after administration of Compound A. The primary endpoint was the area under the plasma concentration-time curve (AUC) of Compound A from the administration time extrapolated to infinity. inf ) and maximum plasma concentration (C maxSecondary endpoints included additional PK parameters and safety and tolerability.

[0711] A total of 30 volunteers were enrolled. Analysis populations included food effect (n=14), PPI effect (n=16), and safety (n=30). max Time to reach (T max ) median values ​​were approximately 4 hours later in the fed state than in the fasted state (12 hours vs. 7.75 hours), and C max and AUC inf The C increased 3.9-fold and 3.1-fold, respectively (Table 2). The inter-individual variability of PK was lower under fed conditions than under fasted conditions. When Compound A was combined with esomeprazole, the C max and AUC inf was slightly decreased (approximately 20% and 11%, respectively; Table 2), and T max The median delay was 3 hours (10 hours vs. 7 hours).

[0712] Compared with fasting, food improved the absorption of Compound A, increasing peak concentrations and the extent of systemic exposure while simultaneously reducing PK variability. Co-administration with esomeprazole slightly decreased peak concentrations and the extent of systemic exposure of Compound A when administered with food.

[0713] The effects of food and PPIs on the PK of Compound A were evaluated in healthy participants. The PK results are shown in Tables 2 and 3 and are summarized here.

[0714] After a single dose of 200 mg of Compound A under fed (high-fat) and fasted conditions, median peak plasma concentrations were reached at 12 hours and 7.75 hours, respectively. Food significantly increased the C of Compound A. max increased approximately fourfold (142 ng / mL vs. 36 ng / mL), and the extent of systemic exposure increased approximately threefold (AUC inf (10,590 h*ng / mL vs. 3,457 h*ng / mL). Food also reduced the variability of Compound A's PK. In both fed and fasted conditions, Com...

Claims

1. 1. A method for treating prostate cancer in a subject, comprising administering to said subject in need thereof Compound A; 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

2. 1. A method for treating prostate cancer in a subject, comprising administering to said subject in need thereof Compound A; 【Chemistry 2】 administering a therapeutically effective amount of the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

3. 1. A method of treating prostate cancer in a subject, comprising administering to said subject in need thereof (i) Compound A, 【Transformation 3】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

4. 1. A method of treating prostate cancer in a subject, comprising administering to said subject in need thereof (i) Compound A, 【Chemistry 4】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

5. The method according to any one of claims 1 to 4, wherein the prostate cancer is prostate adenocarcinoma.

6. The method according to any one of claims 1 to 4, wherein the prostate cancer is metastatic prostate cancer.

7. The method according to any one of claims 1 to 4, wherein the prostate cancer is castration-resistant prostate cancer.

8. The method of any one of claims 1 to 4, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

9. The method of any one of claims 1 to 4, wherein the prostate cancer is advanced metastatic castration-resistant prostate cancer.

10. 1. A method for treating prostate cancer in a subject, comprising administering to said subject in need thereof Compound A; 【Transformation 5】 or a pharmaceutically acceptable salt thereof, the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

11. 1. A method for treating prostate cancer in a subject, comprising administering to said subject in need thereof Compound A; 【Transformation 6】 administering a therapeutically effective amount of the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

12. 1. A method of treating prostate cancer in a subject, comprising administering to said subject in need thereof (i) Compound A, 【Transformation 7】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

13. 1. A method of treating prostate cancer in a subject, comprising administering to said subject in need thereof (i) Compound A, 【Transformation 8】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

14. The method according to any one of claims 10 to 13, wherein the prostate cancer is castration-sensitive prostate cancer.

15. The method according to any one of claims 10 to 13, wherein the prostate cancer is metastatic castration-sensitive prostate cancer.

16. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject, comprising administering to said subject in need thereof Compound A, 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

17. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject, comprising administering to said subject in need thereof Compound A, 【Chemistry 10】 administering a therapeutically effective amount of The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

18. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

19. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 12】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

20. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer is NHA-naive metastatic prostate cancer.

21. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer is NHA-naive castration-resistant prostate cancer.

22. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer is NHA-naive castration-sensitive prostate cancer.

23. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer is NHA-naive metastatic castration-resistant prostate cancer.

24. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer is NHA-naive metastatic castration-sensitive prostate cancer.

25. 20. The method of any one of claims 16 to 19, wherein the NHA-naive prostate cancer has not been previously treated with a second-generation antiandrogen.

26. 20. The method of any one of claims 16-19, wherein the NHA-naive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker.

27. 20. The method of any one of claims 16-19, wherein the NHA-naive prostate cancer has not been previously treated with abiraterone acetate.

28. 28. The method of any one of claims 16 to 27, wherein the NHA-naive prostate cancer has not previously been treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

29. 28. The method of any one of claims 16 to 27, wherein the NHA-naive prostate cancer has not been previously treated with an anti-cancer drug.

30. 28. The method of any one of claims 16 to 27, wherein the subject has not previously been administered an androgen biosynthesis inhibitor or an androgen receptor blocker.

31. 28. The method of any one of claims 16-27, wherein the subject has not previously been administered abiraterone acetate.

32. 28. The method of any one of claims 16 to 27, wherein the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

33. The method of any one of claims 16 to 27, wherein the subject has not previously been administered an anti-cancer drug.

34. 34. The method of any one of claims 1 to 33, wherein a therapeutically effective amount of Compound A is orally administered to the subject.

35. 34. The method of any one of claims 1 to 33, wherein the therapeutically effective amount of Compound A is administered to the subject once daily, twice daily, three times daily, or four times daily.

36. 36. The method of any one of claims 1 to 35, wherein the therapeutically effective amount of Compound A is administered to the subject once daily.

37. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

38. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 250 mg.

39. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is from about 250 mg to about 500 mg.

40. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is from about 500 mg to about 750 mg.

41. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 100 mg.

42. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 150 mg.

43. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 200 mg.

44. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 300 mg.

45. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 320 mg.

46. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 400 mg.

47. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 480 mg.

48. 37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of Compound A is about 500 mg.

49. 49. The method of any one of claims 1 to 48, wherein the subject is in a fed state at the time of administration.

50. The method of any one of claims 1 to 48, wherein the subject is fasting at the time of administration.

51. 51. The method of any one of claims 1 to 50, wherein the prostate cancer comprises at least one somatic AR tumor mutation.

52. 51. The method of any one of claims 1 to 50, wherein the subject has prostate cancer and at least one somatic AR tumor mutation.

53. 53. The method of claim 51 or 52, wherein the at least one somatic AR tumor mutation is a missense mutation in the AR ligand binding domain.

54. The at least one somatic AR tumor mutation is selected from the group consisting of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, E898X, and any combination thereof, wherein "X" is selected from the group consisting of alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methylalanine (M), methylamino acid (Y), methylamino acid (Y), methylamino acid (M ...

54. The method of any one of claims 51 to 53, wherein the amino acid residue other than the wild-type residue at that position is selected from thionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

55. 54. The method of any one of claims 51 to 53, wherein the at least one somatic AR tumor mutation is selected from the group consisting of L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, E898G, and any combination thereof.

56. 54. The method of any one of claims 51-53, wherein the at least one somatic AR tumor mutation is selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof.

57. the at least one somatic AR tumor mutation is: (i) L702H, (ii) T878A, (iii) T878S, (iv) H875Y, (v) L702H and T878A, (vi) L702H and T878S, (vii) L702H and H875Y, (viii) T878A and H875Y; (ix) T878S and H875Y; (x) L702H, T878A, and H875Y, or (xi) L702H, T878S, and H875Y.

58. 58. The method of any one of claims 51 to 57, wherein the at least one somatic AR tumor mutation is L702H.

59. 59. The method of any one of claims 3-9, 12-15, or 18-58, wherein the therapeutically effective amount of abiraterone acetate is from about 250 mg to about 1500 mg.

60. 60. The method of any one of claims 3-9, 12-15, or 18-59, wherein the therapeutically effective amount of abiraterone acetate is about 1000 mg.

61. 61. The method of any one of claims 3-9, 12-15, or 18-60, wherein the therapeutically effective amount of abiraterone acetate is administered orally to the subject.

62. 62. The method of any one of claims 3-9, 12-15, or 18-61, wherein the therapeutically effective amount of abiraterone acetate is administered to the subject once daily.

63. 63. The method of any one of claims 3-9, 12-15, or 18-62, further comprising administering to the subject a corticosteroid.

64. 64. The method of claim 63, wherein about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of the corticosteroid is administered to the subject.

65. 65. The method of claim 63 or 64, wherein the corticosteroid is administered orally to the subject once daily.

66. 66. The method of any one of claims 63-65, wherein the corticosteroid is administered orally to the subject twice daily.

67. 67. The method of any one of claims 63 to 66, wherein the corticosteroid is prednisone, prednisolone, methylprednisolone, cortisone, cortisol, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

68. 68. The method of any one of claims 63 to 67, wherein the corticosteroid is prednisone.

69. 68. The method of any one of claims 63 to 67, wherein the corticosteroid is prednisolone.

70. 70. The method of any one of claims 1 to 69, wherein the subject discontinues use of a PPI before initiating administration of Compound A, or a pharmaceutically acceptable salt thereof.

71. 71. The method of claim 70, wherein the PPI is esomeprazole.

72. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, the prostate cancer harboring at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

73. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, 【Chemistry 14】 administering a therapeutically effective amount of the prostate cancer harboring at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

74. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer harboring at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

75. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 16】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer harboring at least one somatic AR tumor mutation is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or progressive metastatic castration-resistant prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

76. 76. The method of any one of claims 72 to 75, wherein the prostate cancer harboring at least one somatic AR tumor mutation is prostate adenocarcinoma.

77. 76. The method of any one of claims 72 to 75, wherein the prostate cancer harboring at least one somatic AR tumor mutation is metastatic prostate cancer.

78. 76. The method of any one of claims 72 to 75, wherein the prostate cancer harboring at least one somatic AR tumor mutation is castration-resistant prostate cancer.

79. 76. The method of any one of claims 72 to 75, wherein the prostate cancer harboring at least one somatic AR tumor mutation is metastatic castration-resistant prostate cancer.

80. 76. The method of any one of claims 72 to 75, wherein the prostate cancer harboring at least one somatic AR tumor mutation is advanced metastatic castration-resistant prostate cancer.

81. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, the prostate cancer harboring at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

82. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, [Chemistry 18] administering a therapeutically effective amount of the prostate cancer harboring at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

83. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer harboring at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

84. 1. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 20】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; the prostate cancer harboring at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

85. 85. The method of any one of claims 81 to 84, wherein the prostate cancer harboring at least one somatic AR tumor mutation is castration-sensitive prostate cancer.

86. 85. The method of any one of claims 81 to 84, wherein the prostate cancer harboring at least one somatic AR tumor mutation is metastatic castration-sensitive prostate cancer.

87. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, 【Chemistry 21】 or a pharmaceutically acceptable salt thereof, The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

88. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof Compound A, 【Chemistry 22】 administering a therapeutically effective amount of The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

89. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 23】 or a pharmaceutically acceptable salt thereof, and (ii) administering a therapeutically effective amount of abiraterone acetate; The method, wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

90. 1. A method for treating novel hormonal agent (NHA) naive prostate cancer in a subject having at least one somatic AR tumor mutation, comprising administering to said subject in need thereof: (i) Compound A, 【Chemistry 24】 a therapeutically effective amount of (ii) administering a therapeutically effective amount of abiraterone acetate; The method, wherein the therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

91. The method of any one of claims 87 to 90, wherein the NHA-naive prostate cancer harboring at least one somatic AR tumor mutation is NHA-naive metastatic prostate cancer.

92. The method of any one of claims 87 to 90, wherein the NHA-naive prostate cancer harboring at least one somatic AR tumor mutation is NHA-naive castration-resistant prostate cancer.

93. The method of any one of claims 87 to 90, wherein the NHA-naive prostate cancer harboring at least one somatic AR tumor mutation is NHA-naive castration-sensitive prostate cancer.

94. The method of any one of claims 87 to 90, wherein the NHA-naive prostate cancer harboring at least one somatic AR tumor mutation is NHA-naive metastatic castration-resistant prostate cancer.

95. The method of any one of claims 87 to 90, wherein the NHA-naive prostate cancer harboring at least one somatic AR tumor mutation is NHA-naive metastatic castration-sensitive prostate cancer.

96. 96. The method of any one of claims 72 to 95, wherein the at least one somatic AR tumor mutation is a missense mutation in the AR ligand binding domain.

97. The at least one somatic AR tumor mutation is selected from the group consisting of L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, E898X, and any combination thereof, wherein "X" is selected from the group consisting of alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methylalanine (M), methylamino acid (Y), methylamino acid (Y), methylamino acid (M ...

97. The method of any one of claims 72-96, wherein the amino acid residue other than the wild-type residue at that position is selected from thionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

98. 97. The method of any one of claims 72-96, wherein the at least one somatic AR tumor mutation is selected from the group consisting of L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, E898G, and any combination thereof.

99. 97. The method of any one of claims 72-96, wherein the at least one somatic AR tumor mutation is selected from the group consisting of L702H, M895V, W742C, S889G, M750V, M896V, T878A, F877L, D891H, H875Y, and any combination thereof.

100. the at least one somatic AR tumor mutation is: (i) L702H, (ii) T878A, (iii) T878S, (iv) H875Y, (v) L702H and T878A, (vi) L702H and T878S, (vii) L702H and H875Y, (viii) T878A and H875Y; (ix) T878S and H875Y; (x) L702H, T878A, and H875Y, or (xi) L702H, T878S, and H875Y.

101. 101. The method of any one of claims 72 to 100, wherein the at least one somatic AR tumor mutation is L702H.

102. (a) Compound A, 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, and (b) abiraterone acetate, 1. A combined preparation for simultaneous, separate or sequential use in a method of treating prostate cancer in a subject, comprising: The combination preparation, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

103. The method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) the combination formulation of claim 102, comprising about 250 mg to about 1500 mg of abiraterone acetate administered orally once daily.

104. The method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) The combination formulation of claim 102 or 103, comprising about 1000 mg of abiraterone acetate administered orally once daily.

105. (a) Compound A, 【Chemistry 26】 or a pharmaceutically acceptable salt thereof, and (b) abiraterone acetate, A combination preparation for simultaneous, separate or sequential use in the treatment of prostate cancer in a subject who is naive to novel hormonal agents (NHA).

106. The method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) the combination formulation of claim 105, comprising about 250 mg to about 1500 mg of abiraterone acetate administered orally once daily.

107. The method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) The combination formulation of claim 105 or 106, comprising about 1000 mg of abiraterone acetate administered orally once daily.

108. The combination preparation according to any one of claims 105 to 107, wherein the novel hormone agent (NHA)-naive prostate cancer is NHA-naive metastatic prostate cancer, NHA-naive castration-resistant prostate cancer, NHA-naive castration-sensitive prostate cancer, NHA-naive metastatic castration-resistant prostate cancer, or NHA-naive metastatic castration-sensitive prostate cancer.

109. Compound A for use in a method for treating prostate cancer in a subject; 【Chemistry 27】 or a pharmaceutically acceptable salt thereof, wherein the method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) comprising a once-daily oral administration of about 250 mg to about 1500 mg of abiraterone acetate; The compound A, or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

110. Compound A for use in a method for treating prostate cancer in a subject; 【Chemistry 28】 or a pharmaceutically acceptable salt thereof, wherein the method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) comprising a once-daily oral administration of about 1000 mg of abiraterone acetate; The compound A, or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, advanced metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

111. Compound A for use in a method for treating novel hormonal agent (NHA) naive prostate cancer in a subject; 【Chemistry 29】 or a pharmaceutically acceptable salt thereof, wherein the method comprises: (i) once-daily oral administration of about 5 mg to about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof; and (ii) Compound A, or a pharmaceutically acceptable salt thereof, comprising a once-daily oral administration of about 250 mg to about 1500 mg of abiraterone acetate.

112. Compound A for use in a method for treating novel hormonal agent (NHA) naive prostate cancer in a subject; 【Transformation 30】 or a pharmaceutically acceptable salt thereof, wherein the method comprises: (i) oral administration of about 5 mg to about 750 mg of Compound A once daily; and (ii) Compound A, or a pharmaceutically acceptable salt thereof, comprising about 1000 mg of abiraterone acetate administered orally once daily.

113. The compound for use according to claim 111 or 112, wherein the prostate cancer naive to novel hormonal agents (NHAs) is metastatic prostate cancer naive to NHAs, castration-resistant prostate cancer naive to NHAs, castration-sensitive prostate cancer naive to NHAs, metastatic castration-resistant prostate cancer naive to NHAs, or metastatic castration-sensitive prostate cancer naive to NHAs.

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