Compounds and methods for targeted degradation of androgen receptors

Abstract

The present disclosure relates to methods of treating prostate cancer, including prostate cancer comprising at least one somatic AR tumor mutation, in a subject, , for example, 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, prostate cancer that has not been treated with a novel hormone agent (NHA), metastatic prostate cancer that has not been treated with NHA; the present invention relates to methods of treating a castration-resistant prostate cancer, a castration-sensitive prostate cancer, a metastatic castration-resistant prostate cancer, and a metastatic castration-sensitive prostate cancer, where the methods comprise administering to a subject in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. And a # imgabs0 # compound A.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 418,926, filed on October 24, 2022, U.S. Provisional Application No. 63 / 418,927, filed on October 24, 2022, U.S. Provisional Application No. 63 / 434,813, filed on December 22, 2022, U.S. Provisional Application No. 63 / 493,309, filed on March 30, 2023, U.S. Provisional Application No. 63 / 496,008, filed on April 13, 2023, U.S. Provisional Application No. 63 / 506,829, filed on June 7, 2023, U.S. Provisional Application No. 63 / 582,504, filed on September 13, 2023, and U.S. Provisional Application No. 63 / 592,176, filed on October 21, 2023. The contents of the said applications are hereby incorporated by reference in their entirety into this application.

[0003] Incorporation of Sequence Listing by Reference

[0004] The content of the electronic sequence listing (file name: "ARVN - 016 - 001WO_ST26.xml", created on October 20, 2023, and with a size of 2,925 bytes) is hereby incorporated by reference in its entirety. Technical Field

[0005] The present disclosure provides methods for treating prostate cancer using bifunctional compounds. Background of the Invention

[0007] Most small - molecule drugs bind to enzymes or receptors in a tight and well - defined pocket. On the other hand, it is well known that protein - protein interactions are difficult to target with small molecules due to the large contact surface of small molecules and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination and are thus attractive therapeutic targets. The development of E3 ligase ligands has proven challenging, in part because they must disrupt protein - protein interactions. However, recent developments have provided specific ligands that bind to these ligases.

[0008] One E3 ubiquitin ligase with therapeutic potential is cereblon. Cereblon is a protein encoded by the CRBN gene in humans. Thalidomide and its analogs (e.g., pomalidomide and lenalidomide) are known to bind to cereblon. These agents bind to cereblon, altering the specificity of the complex, thereby inducing ubiquitination and degradation of transcription factors required for the growth of multiple myeloma. Indeed, higher expression of cereblon is associated with increased efficacy of imide drugs in treating multiple myeloma.

[0009] The androgen receptor (AR) belongs to the nuclear hormone receptor family and is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782 - 97; Vitam. Horm. 1999, 55:309 - 52.). In the absence of androgen, AR binds to heat shock protein 90 (Hsp90) in the cytosol. When androgen binds to AR, its conformation changes, releasing AR from Hsp90 and exposing the nuclear localization signal (NLS). The latter enables AR to translocate into the nucleus, where AR acts as a transcription factor to promote the gene expression responsible for male sexual characteristics (Endocr. Rev. 1987, 8(1):1 - 28; Mol. Endocrinol. 2002, 16(10), 2181 - 7). AR deficiency leads to androgen insensitivity syndrome, formerly known as testicular feminization.

[0010] Although AR is responsible for the development of male sexual characteristics, it is also a well - established oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276 - 308). The commonly measured target gene for AR activity is the secreted prostate - specific antigen (PSA) protein. Current treatment regimens for prostate cancer involve inhibiting the androgen - AR axis by two methods. The first method 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 still develop resistance and experience disease progression. An alternative approach for treating prostate cancer involves eliminating the AR protein.

[0011] Since AR is a key driver of tumorigenesis in multiple forms of prostate cancer, its elimination should produce a therapeutic beneficial response. There is a continuing need in the art for effective treatments for diseases, especially cancer, prostate cancer, and Kennedy's Disease.

[0012] However, non - specific effects and the complete inability to target and regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer agents. Thus, small - molecule therapeutic agents that utilize or enhance the substrate specificity of cereblon and are at the same time "tunable" to specifically target and regulate multiple protein classes would be very useful as therapeutic agents.

[0013] In patients with prostate cancer, over 70 different somatic missense AR tumor mutations have been identified (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 result in reduced ligand specificity, enabling AR to function independently of androgens. Such AR tumor mutations provide tumor cells with the ability to proliferate in an androgen-depleted environment, and thus prostate cancer therapies that block or reduce androgen levels (e.g., luteinizing hormone-releasing hormone agonists) are selected. Therefore, an increased frequency of AR tumor mutations is observed in patients with advanced androgen-independent tumors compared to patients with early-stage prostate cancer (Taplin, M.E. et al. N. Engl. J. Med. (1995) 332: 1393-1398; Marcelli, M. et al. Cancer Res. (2000) 60: 944-949). Summary of the Invention

[0014] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of 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, or progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0015] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0016] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0017] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) A therapeutically effective amount of Compound A, ; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0018] In some embodiments, the prostate cancer is prostate adenocarcinoma.

[0019] In some embodiments, the prostate cancer is metastatic prostate cancer.

[0020] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0021] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0022] In some embodiments, the prostate cancer is progressive metastatic castration-resistant prostate cancer.

[0023] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0024] In one aspect, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0025] On the one hand, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0026] On the one hand, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0027] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0028] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0029] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0030] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0031] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0032] In one aspect, the present application relates to a method for treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0033] In some embodiments, the prostate cancer that has not been treated with NHA is metastatic prostate cancer that has not been treated with NHA.

[0034] In some embodiments, the prostate cancer that has not been treated with NHA is castration-resistant prostate cancer that has not been treated with NHA.

[0035] In some embodiments, the prostate cancer that has not been treated with NHA is castration-sensitive prostate cancer that has not been treated with NHA.

[0036] In some embodiments, the prostate cancer that has not been treated with NHA is metastatic castration-resistant prostate cancer that has not been treated with NHA.

[0037] In some embodiments, the prostate cancer that has not been treated with NHA is metastatic castration-sensitive prostate cancer that has not been treated with NHA.

[0038] In some embodiments, the prostate cancer that has not been treated with NHA has not been previously treated with second-generation antiandrogens.

[0039] In some embodiments, the prostate cancer that has not been treated with NHA has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0040] In some embodiments, the prostate cancer that has not been treated with NHA has not been previously treated with abiraterone acetate.

[0041] In some embodiments, the prostate cancer that has not been treated with NHA has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0042] In some embodiments, the prostate cancer that has not been treated with NHA has not been previously treated with an anticancer agent.

[0043] In some embodiments, the subject has not previously been administered an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0044] In some embodiments, the subject has not previously been administered abiraterone acetate.

[0045] In some embodiments, the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0046] In some embodiments, the subject has not previously been administered an anti-cancer agent.

[0047] In some embodiments, a therapeutically effective amount of Compound A is orally administered to the subject.

[0048] In some embodiments, a therapeutically effective amount of Compound A is administered to the subject once, twice, three times, or four times daily.

[0049] In some embodiments, a therapeutically effective amount of Compound A is administered to the subject once daily.

[0050] In some embodiments, the therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0051] In some embodiments, the therapeutically effective amount of Compound A is from about 5 mg to about 250 mg.

[0052] In some embodiments, the therapeutically effective amount of Compound A is from about 250 mg to about 500 mg.

[0053] In some embodiments, the therapeutically effective amount of Compound A is from about 500 mg to about 750 mg.

[0054] In some embodiments, the therapeutically effective amount of Compound A is about 100 mg.

[0055] In some embodiments, the therapeutically effective amount of Compound A is about 150 mg.

[0056] In some embodiments, the therapeutically effective amount of Compound A is about 200 mg.

[0057] In some embodiments, the therapeutically effective amount of Compound A is about 300 mg.

[0058] In some embodiments, the therapeutically effective amount of Compound A is about 320 mg.

[0059] In some embodiments, the therapeutically effective amount of Compound A is about 400 mg.

[0060] In some embodiments, a therapeutically effective amount of Compound A is about 480 mg.

[0061] In some embodiments, a therapeutically effective amount of Compound A is about 500 mg.

[0062] In some embodiments, the subject is in a fed state at the time of administration.

[0063] In some embodiments, the subject is in a fasted state at the time of administration.

[0064] In some embodiments, the prostate cancer comprises at least one somatic AR tumor mutation.

[0065] In some embodiments, the subject with prostate cancer comprises at least one somatic AR tumor mutation.

[0066] In some embodiments, the at least one somatic AR tumor mutation is an AR ligand-binding domain missense mutation.

[0067] 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, 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).

[0068] 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.

[0069] 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.

[0070] In some embodiments, the at least one somatic AR tumor mutation is

[0071] (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.

[0072] In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0073] In some embodiments, a therapeutically effective amount of abiraterone acetate is from about 250 mg to about 1500 mg.

[0074] In some embodiments, a therapeutically effective amount of abiraterone acetate is about 1000 mg.

[0075] In some embodiments, a therapeutically effective amount of abiraterone acetate is orally administered to the subject.

[0076] In some embodiments, a therapeutically effective amount of abiraterone acetate is administered to the subject once daily.

[0077] In some embodiments, the method of the present application further comprises administering a corticosteroid to the subject.

[0078] In some embodiments, in the method of claim 59, 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 a corticosteroid is administered to the subject.

[0079] In some embodiments, the corticosteroid is orally administered to the subject once daily.

[0080] In some embodiments, the corticosteroid is orally administered to the subject twice daily.

[0081] In some embodiments, the corticosteroid is prednisone, prednisolone, methylprednisolone, cortisone, cortisol, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, desoxycorticosterone acetate, aldosterone, or beclomethasone.

[0082] In some embodiments, the corticosteroid is prednisone.

[0083] In some embodiments, the corticosteroid is prednisolone.

[0084] In some embodiments, the method of the present application includes the subject discontinuing the use of PPI before starting the administration of compound A or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the PPI is esomeprazole.

[0086] In one aspect, the present application relates to a method of treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, , 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0087] In one aspect, the present application relates to a method of treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, ; 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0088] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0089] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0090] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is prostate adenocarcinoma.

[0091] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is metastatic prostate cancer.

[0092] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is castration-resistant prostate cancer.

[0093] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is metastatic castration-resistant prostate cancer.

[0094] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is progressive metastatic castration-resistant prostate cancer.

[0095] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0096] In one aspect, the present application relates to a method for treating prostate cancer having at least one somatic AR tumor mutation in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; wherein the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0097] In one aspect, the present application relates to a method for treating prostate cancer having at least one somatic AR tumor mutation in a subject, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0098] In one aspect, the present application relates to a method for treating prostate cancer having at least one somatic AR tumor mutation in a subject, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0099] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is castration-sensitive prostate cancer.

[0100] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation is metastatic castration-sensitive prostate cancer.

[0101] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation and not previously treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0102] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation and not previously treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, ; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0103] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation and not previously treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0104] On the one hand, the present application relates to a method for treating prostate cancer in a subject having at least one somatic AR tumor mutation and not previously treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

[0105] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation and not previously treated with NHA is metastatic prostate cancer not previously treated with NHA.

[0106] In some embodiments, the prostate cancer having at least one somatic AR tumor mutation and not previously treated with NHA is castration-resistant prostate cancer not previously treated with NHA.

[0107] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation that has not received NHA treatment is castration-sensitive prostate cancer that has not received NHA treatment.

[0108] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation that has not received NHA treatment is metastatic castration-resistant prostate cancer that has not received NHA treatment.

[0109] In some embodiments, the prostate cancer with at least one somatic AR tumor mutation that has not received NHA treatment is metastatic castration-sensitive prostate cancer that has not received NHA treatment.

[0110] In some embodiments, the at least one somatic AR tumor mutation is a missense mutation in the AR ligand-binding domain.

[0111] 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, 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).

[0112] 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.

[0113] 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.

[0114] 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.

[0115] In some embodiments, the at least one somatic AR tumor mutation is

[0116] (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.

[0117] In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0118] In one aspect, the present application relates to a combination preparation: (a) Compound A, or a pharmaceutically acceptable salt thereof; and (b) Abiraterone acetate; for use simultaneously, separately, or sequentially in a method of 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, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0119] In some embodiments, the method comprises: (i) orally administering about 5 mg to about 750 mg of Compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily.

[0120] In some embodiments, the method comprises: (i) Administering orally about 5 mg to about 750 mg of Compound A once daily; and (ii) Administering orally about 1000 mg of abiraterone acetate once daily.

[0121] In one aspect, the present application relates to a combination preparation: (a) Compound A, or a pharmaceutically acceptable salt thereof; and (b) Abiraterone acetate; for use simultaneously, separately or sequentially in a method of treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA).

[0122] In some embodiments, the method comprises: (i) Administering orally about 5 mg to about 750 mg of Compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) Administering orally about 250 mg to about 1500 mg of abiraterone acetate once daily.

[0123] In some embodiments, the method comprises: (i) Administering orally about 5 mg to about 750 mg of Compound A once daily; and (ii) Administering orally about 1000 mg of abiraterone acetate once daily.

[0124] In some embodiments, the prostate cancer that has not received treatment with a novel hormonal agent (NHA) is metastatic prostate cancer that has not received NHA treatment, castration-resistant prostate cancer that has not received NHA treatment, castration-sensitive prostate cancer that has not received NHA treatment, metastatic castration-resistant prostate cancer that has not received NHA treatment, or metastatic castration-sensitive prostate cancer that has not received NHA treatment.

[0125] In one aspect, the present application relates to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method comprises: (i) Administering orally about 5 mg to about 750 mg of Compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) Administering orally 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, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0126] On the one hand, the present application relates to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of Compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily; wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0127] On the one hand, the present application relates to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of Compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily.

[0128] On the one hand, the present application relates to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of Compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily.

[0129] In some embodiments, the prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA) is metastatic prostate cancer that has not received NHA treatment, castration-resistant prostate cancer that has not received NHA treatment, castration-sensitive prostate cancer that has not received NHA treatment, metastatic castration-resistant prostate cancer that has not received NHA treatment, or metastatic castration-sensitive prostate cancer that has not received NHA treatment.

[0130] On the one hand, the present application relates to a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof.

[0131] On the one hand, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering a therapeutically effective amount of Compound A to a subject in need thereof, .

[0132] On the one hand, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering a therapeutically effective amount of Compound A to a subject in need thereof, , or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0133] On the one hand, the present application relates to a method for treating prostate cancer in a subject, the method comprising administering a therapeutically effective amount of Compound A to a subject in need thereof, , wherein the subject is in a fed state at the time of administration.

[0134] On the one hand, the present application relates to a method for treating the following diseases in a subject: 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, prostate cancer not treated with novel hormonal agents (NHA), metastatic prostate cancer not treated with novel hormonal agents (NHA), castration-resistant prostate cancer not treated with novel hormonal agents (NHA), castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), metastatic castration-resistant prostate cancer not treated with novel hormonal agents (NHA), or metastatic castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), the method comprising administering a therapeutically effective amount of Compound A to a subject in need thereof, , or a pharmaceutically acceptable salt thereof.

[0135] On the one hand, the present application relates to a method for treating a subject having the following diseases: 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, prostate cancer not treated with novel hormonal agents (NHA), metastatic prostate cancer not treated with novel hormonal agents (NHA), castration-resistant prostate cancer not treated with novel hormonal agents (NHA), castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), metastatic castration-resistant prostate cancer not treated with novel hormonal agents (NHA), or metastatic castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0136] On the one hand, the present application relates to a method for treating a subject having the following diseases: 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, prostate cancer not treated with novel hormonal agents (NHA), metastatic prostate cancer not treated with novel hormonal agents (NHA), castration-resistant prostate cancer not treated with novel hormonal agents (NHA), castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), metastatic castration-resistant prostate cancer not treated with novel hormonal agents (NHA), or metastatic castration-sensitive prostate cancer not treated with novel hormonal agents (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, .

[0137] On the one hand, the present application relates to a method for treating a subject having the following diseases: 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, prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , wherein the subject is in a fed state at the time of administration.

[0138] On the one hand, the present application relates to a method for treating a subject having the following diseases: prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof.

[0139] On the one hand, the present application relates to a method for treating a subject having the following diseases: prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0140] On the one hand, the present application relates to a method for treating the following diseases in a subject: prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, .

[0141] On the one hand, the present application relates to a method for treating the following diseases in a subject: prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , wherein the subject is in a fed state at the time of administration.

[0142] On the one hand, the present application relates to a method for treating the following diseases in a subject: prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof, wherein the subject with prostate cancer comprises at least one somatic AR tumor mutation.

[0143] On the one hand, the present application relates to a method for treating a subject having the following diseases: prostate cancer not treated with a novel hormonal agent (NHA), metastatic prostate cancer not treated with a novel hormonal agent (NHA), castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration, and wherein the subject having prostate cancer comprises at least one somatic AR tumor mutation.

[0144] On the one hand, the present application relates to a method for treating a subject having the following diseases: prostate cancer not treated with a novel hormonal agent (NHA), metastatic prostate cancer not treated with a novel hormonal agent (NHA), castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , wherein the subject having prostate cancer comprises at least one somatic AR tumor mutation.

[0145] On the one hand, the present application relates to a method for treating a subject having the following diseases: prostate cancer not treated with a novel hormonal agent (NHA), metastatic prostate cancer not treated with a novel hormonal agent (NHA), castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , wherein the subject is in a fed state at the time of administration, and wherein the subject having prostate cancer comprises at least one somatic AR tumor mutation.

[0146] On the one hand, the present application relates to a method for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate.

[0147] In one aspect, the present application relates to a method for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate.

[0148] In one aspect, the present application relates to a method for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0149] In one aspect, the present application relates to a method for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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 for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject suffering from prostate adenocarcinoma comprises at least one somatic AR tumor mutation.

[0151] In one aspect, the present application relates to a method for treating prostate adenocarcinoma in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject suffering from prostate adenocarcinoma comprises at least one somatic AR tumor mutation.

[0152] In one aspect, the present application relates to a method for treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0153] In one aspect, the present application relates to a method for treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0154] In one aspect, the present application relates to a method for treating metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject has not previously been administered a novel hormonal 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.

[0155] 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) a therapeutically effective amount of compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject has not previously been administered a novel hormonal 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 metastatic prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject with metastatic prostate cancer comprises at least one somatic AR tumor mutation.

[0157] 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) a therapeutically effective amount of compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject with metastatic prostate cancer comprises at least one somatic AR tumor mutation.

[0158] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0159] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0160] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0161] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject has not previously been administered a novel hormonal 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 a subject with castration-resistant prostate cancer, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0163] In one aspect, the present application relates to a method of treating a subject with castration-resistant prostate cancer, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0164] In one aspect, the present application relates to a method of treating a subject with metastatic castration-resistant prostate cancer, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0165] In one aspect, the present application relates to a method of treating a subject with metastatic castration-resistant prostate cancer, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0166] On the one hand, the present application relates to a method for treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0167] On the one hand, the present application relates to a method for treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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] On the one hand, the present application relates to a method for treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0169] On the one hand, the present application relates to a method for treating metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0170] On the one hand, the present application relates to a method for treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0171] On the one hand, the present application relates to a method for treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0172] On the one hand, the present application relates to a method for treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0173] On the one hand, the present application relates to a method for treating progressive metastatic castration-resistant prostate cancer in a subject, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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 for treating a subject with progressive metastatic castration-resistant prostate cancer, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject with progressive metastatic castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0175] In one aspect, the present application relates to a method for treating a subject with progressive metastatic castration-resistant prostate cancer, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject with progressive metastatic castration-resistant prostate cancer comprises at least one somatic AR tumor mutation.

[0176] In one aspect, the present application relates to a method for treating a subject with castration-sensitive prostate cancer, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate.

[0177] In one aspect, the present application relates to a method for treating a subject with castration-sensitive prostate cancer, the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0178] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0179] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject, the method comprising: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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 for treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject with castration-sensitive prostate cancer comprises at least one somatic AR tumor mutation.

[0181] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject with castration-sensitive prostate cancer comprises at least one somatic AR tumor mutation.

[0182] In one aspect, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0183] In one aspect, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0184] In one aspect, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; Wherein the subject has not previously been administered a novel hormonal 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.

[0185] On the one hand, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject has not previously been administered a novel hormonal 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.

[0186] On the one hand, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic castration-sensitive prostate cancer comprises at least one somatic AR tumor mutation.

[0187] On the one hand, the present application relates to a method for treating metastatic castration-sensitive prostate cancer in a subject, the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic castration-sensitive prostate cancer comprises at least one somatic AR tumor mutation.

[0188] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0189] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0190] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0191] On the one hand, the present application relates to a method for treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0192] On the one hand, the present application relates to a method for treating metastatic prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0193] On the one hand, the present application relates to a method for treating metastatic prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0194] On the one hand, the present application relates to a method for treating metastatic prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0195] On the one hand, the present application relates to a method for treating metastatic prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0196] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0197] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0198] On the one hand, the present application relates to a method for treating castration-resistant prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having castration-resistant prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0199] In one aspect, the present application relates to a method for treating castration-resistant prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having castration-resistant prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0200] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate.

[0201] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate.

[0202] In one aspect, the present application relates to a method for treating castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having castration-sensitive prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0203] On the one hand, the present application relates to a method for treating a subject with castration-sensitive prostate cancer who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with castration-sensitive prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0204] On the one hand, the present application relates to a method for treating a subject with metastatic castration-resistant prostate cancer who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate.

[0205] On the one hand, the present application relates to a method for treating a subject with metastatic castration-resistant prostate cancer who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate.

[0206] On the one hand, the present application relates to a method for treating a subject with metastatic castration-resistant prostate cancer who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the subject with metastatic castration-resistant prostate cancer who has not been treated with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0207] On the one hand, the present application relates to a method for treating a subject with metastatic castration-resistant prostate cancer who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) a therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having metastatic castration-resistant prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0208] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate.

[0209] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate.

[0210] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having metastatic castration-sensitive prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0211] In one aspect, the present application relates to a method of treating metastatic castration-sensitive prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising administering to the subject: (i) A therapeutically effective amount of Compound A, ; and (ii) A therapeutically effective amount of abiraterone acetate; wherein the subject having metastatic castration-sensitive prostate cancer who has not received treatment with a novel hormonal agent (NHA) comprises at least one somatic AR tumor mutation.

[0212] On the one hand, the present application relates to a method for treating prostate cancer in a subject, wherein the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA), optionally wherein the prostate cancer of the subject has previously been treated with one, two or more NHAs, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof.

[0213] On the one hand, the present application relates to a method for treating prostate cancer in a subject, wherein the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA), optionally wherein the prostate cancer of the subject has previously been treated with one, two or more NHAs, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state at the time of administration.

[0214] On the one hand, the present application relates to a method for treating prostate cancer in a subject, wherein the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA), optionally wherein the prostate cancer of the subject has previously been treated with one, two or more NHAs, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, .

[0215] On the one hand, the present application relates to a method for treating prostate cancer in a subject, wherein the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA), optionally wherein the prostate cancer of the subject has previously been treated with one, two or more NHAs, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A, , wherein the subject is in a fed state at the time of administration.

[0216] In some embodiments, a therapeutically effective amount of compound A is administered orally to the subject.

[0217] In some embodiments, a therapeutically effective amount of compound A is administered to the subject once daily, twice daily, three times daily or four times daily.

[0218] In some embodiments, a therapeutically effective amount of compound A is administered to the subject once daily.

[0219] In some embodiments, a therapeutically effective amount of compound A is administered to the subject as a single dose, or in two, three or four divided doses.

[0220] In some embodiments, a therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

[0221] In some embodiments, a therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0222] In some embodiments, a therapeutically effective amount of Compound A is from about 10 mg to about 500 mg.

[0223] In some embodiments, a therapeutically effective amount of Compound A is from about 20 mg to about 250 mg.

[0224] In some embodiments, a therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0225] In some embodiments, a therapeutically effective amount of Compound A is about 100 mg.

[0226] In some embodiments, a therapeutically effective amount of Compound A is 100 mg.

[0227] In some embodiments, a therapeutically effective amount of Compound A is about 150 mg.

[0228] In some embodiments, a therapeutically effective amount of Compound A is 150 mg.

[0229] In some embodiments, a therapeutically effective amount of Compound A is about 200 mg.

[0230] In some embodiments, a therapeutically effective amount of Compound A is 200 mg.

[0231] In some embodiments, a therapeutically effective amount of Compound A is about 300 mg.

[0232] In some embodiments, a therapeutically effective amount of Compound A is 300 mg.

[0233] In some embodiments, a therapeutically effective amount of Compound A is about 320 mg.

[0234] In some embodiments, a therapeutically effective amount of Compound A is 320 mg.

[0235] In some embodiments, a therapeutically effective amount of Compound A is about 400 mg.

[0236] In some embodiments, a therapeutically effective amount of Compound A is 400 mg.

[0237] In some embodiments, a therapeutically effective amount of Compound A is about 480 mg.

[0238] In some embodiments, a therapeutically effective amount of Compound A is 480 mg.

[0239] In some embodiments, a therapeutically effective amount of Compound A is about 500 mg.

[0240] In some embodiments, a therapeutically effective amount of Compound A is 500 mg.

[0241] In some embodiments, the subject is in a fed state at the time of administration.

[0242] In some embodiments, the subject is in a fasted state at the time of administration.

[0243] In some embodiments, the method of the present application further comprises the step of administering a PPI or H2 compound to the subject. In some embodiments, the method of the present application further comprises the step of administering a PPI or H2 compound to the subject before initiating the administration of Compound A.

[0244] In some embodiments, the method of the present application further comprises the step of stopping the administration of a PPI or H2 compound to the subject before initiating the administration of Compound A. In some embodiments, starting at a time point before initiating the administration of Compound A, the administration of a PPI or H2 compound is stopped in the subject, wherein the time point is at least 10 hours.

[0245] In some embodiments, the method of the present application further comprises the step of reducing the administration of a PPI or H2 compound to the subject before initiating the administration of a therapeutically effective amount of Compound A. In some embodiments, at a time point before initiating the administration of Compound A, the administration of a PPI or H2 compound is reduced in the subject, wherein the time point is at least 10 hours.

[0246] In some embodiments, the PPI or H2 compound is esomeprazole.

[0247] In some embodiments, the method further comprises administering an effective amount of at least one additional anti-cancer agent to the subject in need thereof.

[0248] In some embodiments, the additional anti-cancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate or zoledronate.

[0249] In some embodiments, the prostate cancer comprises at least one somatic AR tumor mutation.

[0250] In some embodiments, the subject with prostate cancer comprises at least one somatic AR tumor mutation.

[0251] 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.

[0252] In one aspect, the present application relates to a method for treating prostate cancer in a subset of subjects with prostate cancer, the method comprising: a. selecting a subject with prostate cancer for treatment based on the subject's somatic AR tumor biomarker status; and b. administering a therapeutically effective amount of compound A, , or a pharmaceutically acceptable salt thereof.

[0253] In one aspect, the present application relates to a method for treating prostate cancer in a subset of subjects with prostate cancer, the method comprising: a. selecting a subject with prostate cancer for treatment based on the subject's somatic AR tumor biomarker status; and b. administering a therapeutically effective amount of compound A, .

[0254] In some embodiments, the subject's somatic AR tumor biomarker status comprises at least one somatic AR tumor mutation.

[0255] 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.

[0256] In some embodiments, the AR biomarker status of the subject is determined by ctDNA analysis, fluorescence in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

[0257] In some embodiments, the AR biomarker status of the subject is determined in a blood sample derived from the subject.

[0258] In some embodiments, the AR biomarker status of the subject is determined in a solid biopsy of a tumor derived from the subject.

[0259] In some embodiments, the subject is also receiving ongoing androgen deprivation therapy (ADT).

[0260] In some embodiments, the ADT includes administering a gonadotropin-releasing hormone analogue or inhibitor to the subject.

[0261] In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is leuprolide, goserelin, triptorelin, histrelin, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the subject has undergone orchiectomy.

[0263] In some embodiments, the subject has histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate.

[0264] In some embodiments, prior to administration of a therapeutically effective amount of Compound A, the subject experienced prostate cancer progression during at least one previously approved systemic therapy for metastatic prostate cancer.

[0265] In some embodiments, prior to administration of a therapeutically effective amount of Compound A, the subject experienced prostate cancer progression during at least two previously approved systemic therapies for metastatic prostate cancer.

[0266] In some embodiments, the previously approved systemic therapy for metastatic prostate cancer is a second-generation androgen inhibitor.

[0267] In some embodiments, the second-generation androgen inhibitor is abiraterone, abiraterone acetate, enzalutamide, darolutamide, apalutamide, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the subject's ECOG performance status is 0 or 1.

[0269] In some embodiments, the subject does not have symptomatic brain metastases that require steroids at a dose higher than physiological replacement.

[0270] In some embodiments, the subject does not have active inflammatory bowel disease.

[0271] In some embodiments, the subject does not have chronic diarrhea.

[0272] In some embodiments, the subject does not have diverticulosis.

[0273] In some embodiments, the subject has not previously undergone gastrectomy.

[0274] In some embodiments, the subject has not previously undergone gastric banding surgery.

[0275] In some embodiments, the subject has not received radiotherapy within four weeks prior to the initial administration of a therapeutically effective amount of Compound A.

[0276] In some embodiments, the subject has not received radiotherapy in which more than about 25% of the subject's bone marrow was irradiated.

[0277] In some embodiments, the subject has not received a study drug within four weeks prior to the initial administration of a therapeutically effective amount of Compound A.

[0278] In some embodiments, the subject has metastatic castration-resistant prostate cancer, wherein the subject's metastatic castration-resistant prostate cancer shows radiological evidence of metastatic disease.

[0279] In some embodiments, the subject has metastatic castration-sensitive prostate cancer, wherein the subject's metastatic castration-sensitive prostate cancer shows radiological evidence of metastatic disease.

[0280] In some embodiments, the prostate cancer is prostate adenocarcinoma.

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

[0282] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0283] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0284] In some embodiments, the metastatic castration-resistant prostate cancer shows radiological evidence of metastatic disease.

[0285] In some embodiments, the prostate cancer is progressive metastatic castration-resistant prostate cancer.

[0286] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0287] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0288] In some embodiments, the metastatic castration-sensitive prostate cancer shows radiological evidence of metastatic disease.

[0289] In some embodiments, the prostate cancer is prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0290] In some embodiments, the prostate cancer is metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0291] In some embodiments, the prostate cancer is castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0292] In some embodiments, the prostate cancer is castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0293] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0294] In some embodiments, the prostate cancer is progressive metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0295] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA).

[0296] In some embodiments, the prostate cancer has not been previously treated with second-generation antiandrogens. In some embodiments, the prostate cancer has not been previously treated with androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the prostate cancer has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, the prostate cancer has not been previously treated with androgen receptor blockers. 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 androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0297] In some embodiments, the subject has not been previously administered second-generation antiandrogens. In some embodiments, the subject has not been previously administered androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the subject has not been previously administered androgen biosynthesis inhibitors. In some embodiments, the subject has not been previously administered androgen receptor blockers. In some embodiments, the subject has not been previously administered abiraterone acetate. In some embodiments, the subject has not been previously administered androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0298] In some embodiments, the prostate cancer is metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with androgen receptor blockers. In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0299] In some embodiments, the prostate cancer is castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0300] In some embodiments, the prostate cancer is castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0301] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0302] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0303] In some embodiments, the second-generation antiandrogen is an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0304] In some embodiments, the androgen biosynthesis inhibitor is abiraterone acetate.

[0305] In some embodiments, the androgen receptor blocker is selected from enzalutamide, darolutamide, and apalutamide.

[0306] In some embodiments, the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA), optionally wherein the subject's prostate cancer has previously been treated with one, two, or more NHAs. BRIEF DESCRIPTION OF THE DRAWINGS

[0307] The drawings are incorporated into and form a part of this specification, illustrate several embodiments of the disclosure, and together with the description are used to explain the principles of the disclosure. The drawings are only for illustrating the embodiments of the disclosure and should not be construed as limiting the disclosure. Other objects, features, and advantages of the disclosure will become apparent from the following detailed description in conjunction with the drawings, which show illustrative embodiments of the disclosure, wherein: Figure 1A and Figure 1B illustrate the general principle of the function of proteolysis-targeting chimeric compounds. Figure 1A represents an exemplary proteolysis-targeting chimeric compound that comprises a protein targeting moiety (PTM; Dark shaded rectangle ), a cereblon ubiquitin ligase binding moiety (CLM; Triangle without shading ), and a linker moiety ( Black line ) that couples or tethers the PTM to the CLM. Figure 1B illustrates the functional use of the proteolysis-targeting chimeric compounds as described herein. Briefly, the CLM recognizes and binds to cereblon (E3 ubiquitin ligase), and the PTM binds and recruits an intracellular target protein, bringing it into close proximity to the cereblon E3 ubiquitin ligase. Typically, the cereblon E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein and, alone or through the E2 protein, catalyzes the attachment of ubiquitin ( Black circle ) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein ( Farthest right ) is then targeted for degradation by the proteasome machinery of the cell.

[0308] Figure 2 is the analysis of compound A in an in vitro AR degradation assay performed in VCaP cells and LNCaP cancer cells carrying AR amplification and AR mutation (T878A) mutations, respectively.

[0309] Figure 3 is a graph showing the ability of compound A to degrade clinically relevant mutant forms of AR.

[0310] Figure 4 is the analysis of compound A in an in vitro cereblon de novo substrate degradation assay performed in Ramos cells and SK-N-DZ cells.

[0311] Figure 5 It is a figure showing the effects of Compound A and enzalutamide in an in vivo VCaP tumor xenograft study in intact mice.

[0312] Figure 6 It shows the effects of Compound A and enzalutamide on plasma PSA levels in samples from an intact VCaP tumor model.

[0313] Figure 7 It shows the best PSA 50 percentage change relative to baseline in patients with AR ligand-binding domain (LBD) mutations, including PSA 50 response in patients with co-existing AR H875 / T878 / L702H mutations.

[0314] Figure 8A 、 Figure 8B and Figure 8C It shows that Compound A inhibits PSA synthesis, blocks prostate cancer proliferation, and induces apoptosis in prostate cancer vertebral-cancer of the prostate (VCaP) cells. Figure 8A It shows the experimental results where 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. The intracellular prostate-specific antigen (PSA) levels were determined using a PSA enzyme-linked immunosorbent assay (ELISA). Figure 8B It shows the experimental results where 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 CellTiter-Glo ® assay. Figure 8C It shows the experimental results where VCaP cells cultured in a medium containing CSS and supplemented with 0.1 nM R1881 were treated with the indicated concentrations of Compound A for 72 hours. Caspase-Glo ® assay was performed to measure the apoptosis level.

[0315] Figure 9The results of a cell proliferation assay are shown, which was conducted under in vitro conditions of a high androgen environment to assess whether compound A can overcome the effects of residual androgens. 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 increasing concentrations of the synthetic androgen R1881. R1881 alone promoted VCaP cell proliferation, indicating that proliferation can be induced by activating the AR signaling pathway. VCaP cells were cultured in medium containing CSS, the designated concentration of R1881, and compound A (300 nM) or enzalutamide (1,000 nM) for 5 days. Cell proliferation was determined using the CellTiter Glo® assay.

[0316] Figure 10 Degradation of the AR protein carrying the clinically relevant point mutations M896V, T878A, F877L, L702H, and H875Y is shown. Plasmids expressing AR WT or the designated AR mutants were stably transfected into HEK293 cells. Each cell line was treated with the designated concentration of compound A for 24 hours. AR levels were determined by AR ELISA without background subtraction. Plasmids expressing AR wild type (WT) or the designated AR mutants were stably transfected into HEK293 cells. Each cell line was treated with the designated concentration of compound A for 24 hours. AR levels were determined by AR ELISA without background subtraction.

[0317] Figure 11 AR degradation is shown in castrated CB17 / SCID male mice bearing VCaP xenografts treated with different single doses of compound A (10, 3, 1, 0.3, 0.1, and 0.03 mg / kg). Tumors were collected 16 hours after dosing and tumor AR levels were determined by western blotting. An antibody recognizing a human mitochondrial-specific antibody (Mito.C) was used as a loading control. Quantification of AR levels by western blotting is shown (lower panel).

[0318] Figure 12 Tumor growth inhibition is shown 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.

[0319] Figure 13 Shows the results of a 10-day prostate regression study in adult rats. Enzalutamide and Compound A were orally administered once daily at the indicated doses. After 10 days of treatment, the prostate tissue of each rat was isolated and weighed. The treatment groups (n = 5 per group) were compared by one-way ANOVA. Note: ns: not significant, : p < 0.05, : p ≤ 0.01.

[0320] Figure 14 Is a graph showing the deep prostate-specific antigen (PSA) decline in patients with metastatic castration-resistant prostate cancer (mCRPC) with wild-type AR. These results support the development of the novel hormonal agent-naïve (NHA-naïve) setting, including metastatic castration-sensitive prostate cancer (mCSPC). The evaluable analysis set included all participants treated with Compound A who had a baseline PSA assessment and at least one post-baseline PSA assessment at C1D28 or later. PSA 90 and PSA 50 and PSA 30 responses were defined as PSA decline = 90% or 50% or 30% relative to the baseline PSA value, respectively.

[0321] Sequence Listing

[0322] All references to amino acid mutations of the androgen receptor are numbered relative to SEQ ID NO: 1, the sequence of which is provided below: Detailed Description

[0323] Definitions

[0324] All references to amino acid mutations of the androgen receptor are numbered relative to SEQ ID NO: 1, which is provided herewith.

[0325] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, either alone or in combination with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to lysine on a target protein and then targets specific substrate proteins to be degraded by the proteasome. Thus, the E3 ubiquitin ligase is responsible for transferring ubiquitin to the target protein, either alone or in complex with an E2 ubiquitin-conjugating enzyme. Generally speaking, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is ligated to the first ubiquitin; a third ubiquitin is ligated to the second ubiquitin, and so on. Polyubiquitination marks the protein for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, where the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome but can instead alter their cellular location or function, for example, by binding to other proteins that have a domain capable of binding ubiquitin. Adding to the complexity, the E3 can target different lysines on ubiquitin to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make the polyubiquitin that is recognized by the proteasome.

[0326] As used herein, "compound", "bifunctional compound", or "compounds of the present disclosure" refers to the compounds disclosed by structure in the following tables and examples.

[0327] The term "substituted" or "optionally substituted" shall independently (i.e., when there is more than one substituent, each substituent is independent of the other substituent) mean one or more substituents (independently up to five substituents, preferably up to three substituents, typically 1 or 2 substituents on a moiety of a compound according to the present disclosure and can include substituents that can themselves be further substituted) at any carbon (or nitrogen) position on a molecule in the context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2, or 3 halogens, especially on an alkyl, especially methyl, such as trifluoromethyl), alkyl (preferably C1-C 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl, including alkylene esters (such that the linkage is on the alkylene, rather than on the ester functional group, which is preferably substituted by C1-C6 alkyl or aryl)), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkylene amines, also including C1-C6 alkyl amines or C1-C6 dialkyl amines, where the alkyl can be substituted by one or two hydroxyl groups) or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) (which can optionally be substituted by a polyethylene glycol chain, which is further attached to an alkyl containing a single halogen, preferably chlorine substituent), hydrazine, amido group (which is preferably substituted by one or two C1-C6 alkyl groups, including carboxamides optionally substituted by one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl) or alkanoic acid (preferably C1-C6 alkyl or aryl). The substituents according to the present disclosure can include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as described elsewhere herein, and R3 is H or C1-C6 alkyl, preferably, R1, R2, R3 herein are C1-C3 alkyl (including isopropyl or tert-butyl). Each of the above groups can be directly attached to the substituted moiety, or alternatively, the substituent can be attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted -(CH2) m - or alternatively, an optionally substituted (OCH2) m -, -(OCH2CH2) m - or -(CH2CH2O) m - group (which can be substituted by any one or more of the above substituents) to the substituted moiety. Alkylene -(CH2) m - or -(CH2) n- A group or other chain (such as an ethylene glycol chain, as identified above) can be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl, which may optionally be substituted by: one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F), or an amino acid side chain as further described herein, and an optionally substituted amide (preferably a carboxamide substituted as described above) or a carbamate group (usually having one or two C0-C6 alkyl substituents, which groups may be further substituted). In certain embodiments, the alkylene group (usually a single methylene) is substituted by one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most commonly methyl or O-methyl, or an amino acid side chain as further described herein. In the present disclosure, a moiety in a molecule can optionally be substituted by up to five substituents, preferably up to three substituents. Most commonly, in the present disclosure, the substituted moiety is substituted by one or two substituents.

[0328] The term "substituted" (each substituent being independent of any other substituent) within its context of use shall also mean C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone (including sulfonamide), keto, carboxy, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, carbamate -O-C(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (especially including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl-substituted amines, which amines may optionally be substituted by one or two hydroxyl groups). Unless otherwise specified in the context, each of these groups contains between 1 and 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (wherein m and n are 1, 2, 3, 4, 5, or 6 in context), -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) nC(O)-NR1R2, -(OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R S is a C1-C6 alkyl or -(CH2) m -NR1R2 group), 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, in context, H or a C1-C6 alkyl (which may optionally be substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" should also mean, in the chemical context of the defined compounds and the substituents used, an optionally substituted aryl or heteroaryl or an optionally substituted heterocyclic group, as further described herein. The alkylene group may also be substituted as further disclosed herein, preferably by an optionally substituted C1-C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, so as to provide a chiral center), a side chain of an amino acid group as further described herein, an amide group or a carbamate group O-C(O)-NR1R2 group (wherein R1 and R2 are as further described herein), although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted by 3 or more substituents, preferably not more than 3 substituents, and preferably by 1 or 2 substituents. It should be noted that where substitution is required (mainly because of valence) at a particular position in the molecule in the compound but the substitution is not specified, the substituent is construed or understood as H, unless the context of the substitution indicates otherwise.

[0329] The term "aryl" or "aromatic" as used herein refers to a substituted (as further described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthryl, etc.), and may be attached to a compound according to the present disclosure at any available stable position on the ring or as otherwise specified in the presented chemical structure. In context, other examples of aryl may include heteroaromatic ring systems, i.e., "heteroaryl" having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be optionally substituted as described above. Heteroaryls that may be mentioned include nitrogen-containing heteroaryls 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, quinazoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridinopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and 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, pyrazolooxazole, imidazolothiazole, thiophenofuran, furanopyrrole, pyridinooxazine, furanopyridine, furanopyrimidine, thiophenopyrimidine, and oxazole, etc., all of which may be optionally substituted.

[0330] The term "substituted aryl" refers to an aromatic carbocyclic group that contains at least one aromatic ring, or multiple fused rings, at least one of which is aromatic, where said ring(s) is / are substituted with one or more substituents. For example, an aryl may contain a substituent selected from: -(CH2) 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, amine, mono- or di-(C1-C6alkyl)amine, where the alkyl on the amine is optionally substituted with: 1 or 2 hydroxy groups or up to three halogen groups (preferably F, Cl), OH, COOH, C1-C6alkyl (preferably CH3), CF3, OMe, OCF3, NO2 or CN groups (where each of these can be substituted at the ortho, meta and / or para positions of the benzene ring, preferably para), an optionally substituted phenyl (the phenyl itself is preferably substituted with a linker group that is connected to the ABM group, including the ULM group) and / or at least one of the following: F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (at the ortho, meta and / or para positions of the benzene ring, preferably para), naphthyl (which can be optionally substituted), an optionally substituted heteroaryl (preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole), an optionally substituted oxazole (including a methyl-substituted oxazole), an optionally substituted thiazole (including a methyl-substituted thiazole), an optionally substituted isothiazole (including a methyl-substituted isothiazole), an optionally substituted pyrrole (including a methyl-substituted pyrrole), an optionally substituted imidazole (including methylimidazole), an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oximidazole or methyloximidazole, an optionally substituted dioxole group (including a methyldioxole group), an optionally substituted triazole group (including a methyl-substituted triazole group), an optionally substituted pyridine group (including a halogen (preferably F) or methyl-substituted pyridine group or an oxypyridine group (where the pyridine group is connected to the phenyl through oxygen)), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indazine or aza-indazine (2, 3 or 4-aza-indazine), an optionally substituted quinoline and combinations thereof.

[0331] The term "heteroaryl / hetaryl" can mean, but is not limited to, an optionally substituted quinoline (which can be connected to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indazine, an optionally substituted aza-indazine (2, 3 or 4-aza-indazine), an optionally substituted benzimidazole, benzodioxole, benzofurazan, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably, methyl-substituted), an optionally substituted dioxole, an optionally substituted triazole, tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably, methyl- and / or mercapto-substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably, substituted with methyl, triisopropylsilyl, optionally substituted -(CH2) m -O-C1-C6alkyl or optionally substituted -(CH2) m-C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), an optionally substituted pyridine (2-, 3- or 4-pyridine) or a group according to the following chemical structure:

[0332] wherein

[0333] S c is CHR SS , NR URE or O; R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O-(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl-C≡C-R a (wherein R a is H or C1-C6 alkyl (preferably C1-C3 alkyl)); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted by 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 said groups being optionally substituted by: 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, wherein each is optionally substituted, and Y C is N or C-R YC wherein R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O-(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl-C≡C-R a (wherein R a is H or C1-C6 alkyl (preferably C1-C3 alkyl)).

[0334] The term "heterocycle" refers to a cyclic group containing at least one heteroatom (e.g., N, O, or S) and can be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moiety is subsumed within the definition of heterocycle, depending on the context of its use. Exemplary heteroaryls were described above.

[0335] Exemplary heterocyclic groups include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxolanyl, dioxolyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, 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, thiane, etc.

[0336] The heterocyclic group may optionally be 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, azide, cyano, halogen, hydroxy, keto, thione, carboxyl, carboxyalkyl, thioaryloxy, thioheteraryloxy, thioheteracyloxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic group, heteracyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo group (=O) and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of azacyclic and heteroaryl include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indene, isoindole, indole, indazole, purine, quinazine, 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, etc., and heterocycles containing N-alkoxy-nitrogen. The term "heterocyclic" also includes bicyclic groups in which any heterocycle is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0337] The term "cycloalkyl" may mean, but is in no way limited to, a monovalent group derived from a monocyclic or polycyclic alkyl or cycloalkane as defined herein, e.g., a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may mean, but is in no way limited to, a monocyclic or polycyclic alkyl and substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, and these general substituents have the same meaning as the corresponding groups defined in this legend.

[0338] "Heterocycloalkyl" means a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. "Substituted heterocycloalkyl" means a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthio, aryl, nitro, mercapto, and sulfo, and these general substituents have the same meaning as the definitions of the corresponding groups as defined in this illustration.

[0339] The term "spiro" or "spirofused cycloalkyl" means a polycyclic alkyl group containing at least two rings, where the two rings share exactly one ring atom. The term "spirohetero" or "spirofused heterocycloalkyl" means a spirofused cycloalkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. Spirofused cycloalkyl and spirofused heterocycloalkyl can be further defined by the number of their rings, such as bicyclic, tricyclic, tetracyclic, etc.

[0340] The term "bridged cycloalkyl" or means a polycyclic alkyl group containing at least two rings, where the two rings share at least three ring atoms. The term "bridged hetero" means a bridged cycloalkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. Bridged cycloalkyl and spirofused heterocycloalkyl can be further defined by the number of their rings, for example, bicyclic, tricyclic, tetracyclic, etc.

[0341] "Halogen" or "halo group" means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0342] "C1-C6 alkyl" means a straight-chain or branched-chain saturated hydrocarbon containing 1-6 carbon atoms. Examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0343] As used herein with respect to the compounds of the present disclosure, "pharmaceutically acceptable salts" means the salt forms of the compounds of the present disclosure and the hydrates of such salt forms with one or more water molecules present. Such salts and hydrated forms retain the biological activity of the compounds of the present disclosure and are biologically or otherwise desirable, i.e., exhibit minimal (if any) toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, aminosulphonate (4,4-diaminostilbene-2,2-disulphonate), benzenesulphonate, benzoate, bicarbonate, bisulphate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulphonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, ethanedisulphonate, ethohexate, esilate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulphate, mucate, naphthalenesulphonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1'-methylene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulphonate, salicylate, stearate, subacetate, succinate, sulphate, sulphonate, suramate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, and valerate.

[0344] The term "isomer" refers to salts and / or compounds having the same composition and molecular weight but different physical and / or chemical properties. The structural differences may lie in the constitution (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). For stereoisomers, the salts of the compounds of the present disclosure may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereoisomers.

[0345] The compounds of the present disclosure may exist in unsolvated as well as solvated forms, such as hydrates.

[0346] "Solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Non-limiting examples of suitable solvates include alcoholates, methanolates, etc. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a substance, in which the water retains its molecular state as H2O, and such a combination can form one or more hydrates. In a hydrate, the water molecules are connected by intermolecular forces, especially hydrogen bridges, through secondary valence states. Solid hydrates contain water in a stoichiometric ratio, i.e., so-called water of crystallization, and the binding states of the water molecules do not have to be equal. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Hydrates of salts of the compounds of the present disclosure are equally suitable.

[0347] As mentioned herein, "isotope derivative" relates to the compounds of the present disclosure, which are isotopically enriched or labeled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in the present application, the compounds of the present disclosure include, for example, compounds that are isotopically enriched or labeled with one or more atoms (such as deuterium).

[0348] As used herein, "treating" describes the management and care of a subject for combating a disease, disorder or condition, and includes reducing or alleviating symptoms or complications, or eliminating the disease, disorder or condition.

[0349] Unless otherwise indicated, as used herein, the term "treatment" means reversing, alleviating or inhibiting the progression of a condition or disorder to which such terms apply, or one or more symptoms of such a condition or disorder. Unless otherwise indicated, as used herein, the term "treatment" refers to the act of "treatment" as just defined above. For example, the term "treat / treating / treatment" can refer to a method of alleviating or eliminating a specific condition and / or one or more of its accompanying symptoms.

[0350] As used herein, "subject" means a human or an animal (in the case of an animal, the subject can be a mammal). In one aspect, the subject is a human. In one aspect, the subject is male.

[0351] Prostate cancer is the uncontrolled growth of cancer cells in the prostate. 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 not treated with a novel hormonal agent (NHA), castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA), castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), metastatic prostate cancer not treated with a novel hormonal agent (NHA), metastatic castration-resistant prostate cancer not treated with a novel hormonal agent (NHA), or metastatic castration-sensitive prostate cancer not treated with a novel hormonal agent (NHA).

[0352] Metastatic prostate cancer or metastasis means that the prostate cancer has spread to other parts of the body outside the prostate, such as bone, lymph nodes, liver, lung, brain.

[0353] Castrate-resistant prostate cancer (Castrate-resistant prostate cancer / castration-resistant prostate cancer / prostate cancer that is castrate- or castration-resistant) is a type of prostate cancer that continues to grow even when the amount of testosterone in the body has been reduced to very low levels.

[0354] 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 been reduced to very low levels.

[0355] Castrate-sensitive prostate cancer (Castrate-sensitive prostate cancer / castration-sensitive prostate cancer / prostate cancer that is castrate- or castration-sensitive; CSPC) is a prostate cancer that can be controlled by reducing the amount of androgens (male hormones) in the body (e.g., by castration), and / or a prostate cancer that requires androgens for growth and stops growing in the absence of androgens. CSPC is also known as androgen-dependent prostate cancer, androgen-sensitive prostate cancer, or hormone-sensitive prostate cancer (HSPC).

[0356] Metastatic castration-sensitive prostate cancer is a type of castrate-sensitive prostate cancer that has metastasized and requires androgens for growth or can be controlled by reducing the amount of androgens in the body (e.g., by castration).

[0357] Prostate cancer that has not been treated with a novel hormonal agent (NHA) is prostate cancer that has not been previously treated with a second-generation anti-androgen, 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.

[0358] Metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA) is metastatic prostate cancer that has not been previously treated with a second-generation anti-androgen, 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.

[0359] Castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) is castration-resistant prostate cancer that has not been previously treated with a second-generation anti-androgen, 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.

[0360] Castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) is castration-sensitive prostate cancer that has not been previously treated with a second-generation anti-androgen, 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.

[0361] Metastatic castration-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA) is metastatic castration-resistant prostate cancer that has not been previously treated with a second-generation anti-androgen, 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.

[0362] Metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA) is metastatic castration-sensitive 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.

[0363] As used herein, "preventing" describes halting the onset of symptoms or complications of the disease, disorder, or condition.

[0364] "Administration" refers to introducing an agent (e.g., a compound of the present disclosure) into a subject. The related terms "administering / administration of" (and grammatical equivalents) refer to direct administration, which can be by a healthcare provider to a subject or self-administration by the subject, and / or indirect administration, which can be the act of prescribing a medication. For example, a doctor who instructs a patient to self-administer a drug and / or provides a prescription for a drug to a patient is administering the drug to the patient.

[0365] The terms "co-administration / co-administrating" or "combination therapy" refer to concurrent administration (administering two or more therapeutic agents simultaneously) and time-varying administration (the administration times of one or more therapeutic agents are different from the administration times of one or more other therapeutic agents), provided that the therapeutic agents are present in the patient's body to some extent, preferably in an effective amount, at the same time. In certain preferred aspects, one or more compounds of the present invention described herein are co-administered in combination with at least one additional bioactive agent, particularly including anti-cancer agents. In particularly preferred aspects, the co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0366] As used herein, "therapeutically effective amount" means 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, that is sufficient to treat, ameliorate, or prevent a designated disease (e.g., prostate cancer), disease symptoms, condition, or disorder, or is sufficient to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The effective amount for a particular subject may depend on the subject's weight, size, and health status; the nature and extent of the disorder; and whether additional therapeutic agents will be administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of a clinician.

[0367] As used herein, "C" max" refers to the maximum (peak) plasma concentration of the specified compound observed in a subject after administration of a defined dose of the compound to the subject.

[0368] 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 (ng x h / mL), where "h" refers to hours.

[0369] As used herein, "AUC τ " refers to the AUC from 0 hours to the end of the dosing interval.

[0370] "AUC 0-24 " means the AUC from 0 hours to 24 hours after administration of a single dose.

[0371] As used herein with respect to oral dosage forms, "controlled release" or "CR" means that the compounds of the present disclosure are released from the dosage form according to a predetermined curve, which may include when and where release occurs after oral administration and / or a specified release rate over a specified time period

[0372] As used herein with respect to the oral dosage forms of the present disclosure, "controlled release agent" means one or more substances or materials that regulate the release of the compounds of the present disclosure from the dosage form. The controlled release agent can be an organic or inorganic, naturally occurring or synthetic material, such as a polymeric material, a triglyceride, a derivative of a triglyceride, a fatty acid and a salt of a fatty acid, talc, boric acid, colloidal silica, and combinations thereof.

[0373] As used herein with respect to the dosage forms of the present disclosure, "enteric coating" means a pH-dependent material that surrounds the core containing the compounds of the present disclosure and remains substantially intact in the acidic environment of the stomach but dissolves in the intestinal pH environment.

[0374] "Gastro-resistant" or "GR" as applied to the CR oral dosage forms described herein means that the release of the compounds of the present disclosure in the subject's stomach should not exceed 5%, 2.5%, 1% or 0.5% of the total amount of the compounds of the present disclosure in the dosage form.

[0375] As used herein, "oral dosage form" means a pharmaceutical product that contains a defined amount (dose) of the compounds of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and inactive components (excipients), formulated in a specific configuration suitable for oral administration, such as an oral tablet, liquid or capsule. In some embodiments, the composition is in the form of a scoreable tablet.

[0376] As used in this disclosure, the term "carrier" encompasses pharmaceutically acceptable excipients and diluents, and refers to a material, composition, or vehicle that participates in carrying or transporting an agent from one organ or body part of a subject to another organ or body part, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0377] As part of a quantitative expression (e.g., "about X"), the term "about" includes any value that is 10% higher or lower than X, and also includes any numerical value between X - 10% and X + 10%. Thus, for example, a weight of about 40 g includes weights between 36 and 44 g. When used herein to denote an amino acid residue in AR, the term "about" means any amino acid residue within the specified 5 amino acid residues. For example, when referring to a continuous amino acid residue extension from about amino acid residue 560 to about amino acid residue 624 of AR, this refers to a continuous amino acid residue extension 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. In some embodiments, the term "about" means any amino acid residue within the specified 3 amino acid residues. In some embodiments, the term "about" means any amino acid residue within the specified 1 amino acid residue.

[0378] Compound A of the present disclosure refers to 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, which has the following structure: (Compound A).

[0379] In some embodiments, Compound A can be prepared as described in U.S. Patent Application Publication No. 2021 / 0196710 A1, which is incorporated herein by reference.

[0380] When applied to a particular dosage form, composition, use, method or process described or claimed herein, "comprising" means that the dosage form, composition, use, method or process includes all of the elements recited in the particular description or claim, but does not exclude other elements. "Consisting essentially of" means that the composition, dosage form, method, use or process described or claimed does not exclude other materials or steps that do not materially affect the physical, pharmacological, pharmacokinetic properties or therapeutic effect recited for the composition, dosage form, method, use or process. "Consisting of" means excluding other ingredients and substantial method or process steps in excess of trace elements.

[0381] The ECOG performance status scale was developed by the Eastern Cooperative Oncology Group as a standard guideline for measuring how a disease affects a patient's ability to perform daily activities. It describes the patient's functional level in terms of their ability to perform self-care, daily activities and physical abilities (walking, working, etc.). Patients are classified on a scale of 1 - 5:

[0382] As used herein to describe a subject's "fasting condition" or "fasting state" means that the subject has not eaten for at least 4 hours prior to the time point of interest (e.g., the time of administration of the compounds of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof)). In one embodiment, a subject in a fasting state has not eaten at any time within at least 6, 8, 10 or 12 hours prior to administration of the compounds of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof).

[0383] As used herein to describe a subject's "feeding condition" or "feeding state" means that the subject has eaten within less than 4 hours prior to the time point of interest (e.g., the time of administration of the compounds of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof)). In one embodiment, a subject in a feeding state has eaten at any time within at least 3, 2, 1 or 0.5 hours prior to administration of the compounds of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof).

[0384] Corticosteroids are a class of steroid hormones, which include steroid hormones produced by humans and other vertebrates, as well as 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, desoxycorticosterone acetate, aldosterone or beclomethasone.

[0385] "Proton pump inhibitor" or "PPI" refers to a member of a class of compounds that reduce or eliminate gastric acid production. In some embodiments, the PPI is omeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole or rabeprazole.

[0386] "H2 antagonist" or "H2 receptor blocker" is collectively referred to as "H2 compound" herein, and refers to a member 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.

[0387] As used herein, "gastric acid regulator" is a collective term for PPIs, H2 compounds and antacids, including those prescribed by doctors and those over-the-counter drugs.

[0388] As used herein, the term "CDK inhibitor" refers to a compound that inhibits an enzyme called cyclin-dependent kinase (CDK) in humans. 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 CDK 4 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.

[0389] As used herein, the term "PARP inhibitor" refers to a compound that inhibits an enzyme called poly ADP ribose polymerase (PARP) in humans. Examples of PARP inhibitors include but are not limited to olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722, E7016, 3-aminobenzamide, mefoliparib and AZD2281.

[0390] As used herein, the term "anticancer agent" is used to describe an anticancer agent, or a therapeutic agent administered in parallel with an anticancer agent (e.g., palonosetron), which can be co-administered and / or co-formulated with the compounds of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) to treat cancer, as well as side effects associated with cancer treatment. These agents include, for example, everolimus, trabectedin, albumin-bound paclitaxel, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 regulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, CDK inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / STAT inhibitor, checkpoint-1 or 2 inhibitor, focal adhesion kinase inhibitor, MAP kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, erlotinib, dasatinib, nilotinib, decatinib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalutumumab, edotecarin, tetrandrine, rupirtecam, pafuramidine, olimersen, tesirine, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gemcitabine, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, anthralin, LY317615, neuradiab, vitespan, Rta744, Sdx 102, talampanel, atrasentan, Xr311, 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, Exemestane, Letrozole, DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperidinomethyl)-Indolyl-Quinoline, 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, Lapatinib, Canertinib, ABX-EGF Antibody, Cetuximab, EKB-569, PKI-166, GW-572016, Lonafarnib, BMS-214662, Tipifarnib; Amifostine, NVP-LAQ824, Suberoyl Analide Hydroxamicacid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, aclarubicin, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin D, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, imatinib (gleevec), gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib (imatinib), leuprorelin, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, sodium porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, azoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD184352, 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 alpha, erythropoietin, granulocyte colony-stimulating factor, zoledronic 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 acetate, immunoglobulin, mechlorethamine, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, altretamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegylated filgrastim, erythropoietin, epoetin alfa, darbepoetin alpha, 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 acetate, flutamide, bicalutamide, nilutamide, pamidronate, and zoledronate. In some embodiments, the anticancer agent is selected from the group consisting of: FLT-3 inhibitor, androgen receptor inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, IGFR TK inhibitor, PI3 kinase inhibitor, AKT inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase inhibitor, VEGF trap antibody, and chemical castration agent.

[0391] In some embodiments, the anti-cancer agent is selected from the group consisting of: temozolomide, capecitabine, irinotecan, tamoxifen, anastrozole, exemestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, asoxifene, fulvestrant, prednisone, abiraterone, abiraterone acetate, enzalutamide, apalutamide, darolutamide, sipuleucel-T, pembrolizumab, nivolumab, cemiplimab, atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, and zoledronate.

[0392] Abiraterone acetate, namely: [(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 trade name Zytiga®, and is suitable for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. The structure of abiraterone acetate is: .

[0393] Abiraterone, namely (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: .

[0394] The article "a / an" is used in the present disclosure to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element.

[0395] Unless otherwise specified, the term "and / or" is used in the present disclosure to mean "and" or "or".

[0396] 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.

[0397] In some embodiments, the subject is a human.

[0398] In some embodiments, the subject is a human diagnosed with prostate cancer.

[0399] In some embodiments, the subject is a human diagnosed with metastatic prostate cancer.

[0400] In some embodiments, the subject is a human diagnosed with castration-resistant prostate cancer.

[0401] In some embodiments, the subject is a human diagnosed with metastatic castration-resistant prostate cancer.

[0402] In some embodiments, the subject is a human diagnosed with castration-sensitive prostate cancer.

[0403] In some embodiments, the subject is a human diagnosed with metastatic castration-sensitive prostate cancer.

[0404] In some embodiments, the subject is a human diagnosed with prostate cancer and has not received treatment with a novel hormonal agent (NHA).

[0405] In some embodiments, the subject is a human diagnosed with castration-sensitive prostate cancer and has not received treatment with a novel hormonal agent (NHA).

[0406] In some embodiments, the subject is a human diagnosed with castration-resistant prostate cancer and has not received treatment with a novel hormonal agent (NHA)

[0407] In some embodiments, the subject is a human diagnosed with metastatic prostate cancer and has not received treatment with a novel hormonal agent (NHA).

[0408] In some embodiments, the subject is a human diagnosed with metastatic castration-resistant prostate cancer and has not received treatment with a novel hormonal agent (NHA).

[0409] In some embodiments, the subject is a human diagnosed with metastatic castration-sensitive prostate cancer and has not received treatment with a novel hormonal agent (NHA).

[0410] The compounds of the present disclosure

[0411] On the one hand, the present application relates to a bifunctional or multifunctional compound that can be used to regulate protein activity by inducing the degradation of a target protein. In some embodiments, the bifunctional compound comprises an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked by a linker moiety as further described herein, wherein the E3 ubiquitin ligase binding moiety is conjugated to the protein targeting moiety, and wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein targeting moiety recognizes a target protein such that degradation of the target protein will occur when the target protein is placed near the ubiquitin ligase, thereby resulting in degradation / inhibition of the effect on the target protein and control of the protein level. In certain embodiments, the bifunctional compound comprises a CLM conjugated (e.g., covalently linked, directly or indirectly) to a chemical linker L, and a PTM, and the compound can be depicted as: PTM-L-CLM CLM recognizes and binds to cereblon (an E3 ubiquitin ligase). PTM is a small molecule protein binding moiety that binds and recruits an intracellular target protein or polypeptide into close proximity to CLM, thereby enabling degradation of the target protein, resulting in ubiquitination of the target protein. In certain embodiments, PTM is an AR binding moiety (ABM).

[0412] In any of the compounds described herein, PTM comprises the following chemical structure: 、 、 、 、 、 、 、 、 、 、 and 。

[0413] In any of the compounds described herein, L comprises the following chemical structure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , and .

[0414] In any of the compounds described herein, CLM comprises the following chemical structure: , , , , , , , , , , , , , , , , , and .

[0415] On the other hand, the present application relates to a bifunctional compound having the following structure: ABM-L-CLM, or a pharmaceutically acceptable salt thereof, wherein: (a) ABM is an androgen receptor (AR) binding moiety having the following structure:

[0416] wherein: Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each independently CR 1 or N; is a 4-6 membered cycloalkyl, C6-C 10 aryl, 4-6 membered heterocycloalkyl or 4-6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl contains 0-4 heteroatoms; Q 6 , Q 7 , Q 8 , Q 9 and Q 10 are each independently CR 3 or N; Each R 1Independently 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 said alkyl or alkoxy is optionally substituted by one or more halogen groups; Each R 2 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 said alkyl or alkoxy is optionally substituted by one or more halogen groups; Each R 3 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 said alkyl or alkoxy is optionally substituted by one or more halogen groups; and n is 0, 1, 2, 3, or 4; (b) L is a chemical linking moiety having the following structure:

[0417] Wherein: ABM is connected to W, and CLM is connected to Z, or ABM is connected to Z, and CLM is connected to W; W is absent or is A 4-7 membered cycloalkyl, 4-7 membered heterocycle, or spirobicyclic heterocycloalkyl, wherein each ring in the spirobicycle is 4-7 membered; X is -CH2- or absent; Y is -NR 6 -, -O-, or absent; Is a 4-7 membered cycloalkyl or 4-7 membered heterocycle; Z is -C(R 7 )2-, -NR 7 -, -O-, or absent; R 6 Is H, straight-chain or branched C 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy-C 1-6 Alkyl or Where Indicates the bond connected to Y, and Indicates the bond connected to Connected bond; Each R 7 Independently selected from the group consisting of: H, straight-chain or branched C 1-6 Alkyl and straight-chain or branched C1-6 Alkoxy; p is 1, 2, 3 or 4; and q is 1, 2, 3, 4 or 5; (c) CLM is a cereblon E3 ubiquitin ligase binding moiety having the following structure:

[0418] wherein: is C6-C 10 aryl, 4- to 7-membered heteroaryl or bridged bicyclic cycloalkyl; indicates that the linking moiety L is attached 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 is optionally substituted by one or more halo groups; 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 is optionally substituted by one or more halo groups; and m is 0, 1, 2, 3 or 4.

[0419] On the other hand, the present application relates to a compound of formula (I):

[0420] (I)

[0421] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0422] In some embodiments, when is pyridyl, is tetramethylcyclobutyl, Q 2 is CR 1 , and Q 4 is CR 1 then R 1 is not chlorine.

[0423] 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.

[0424] In some embodiments, the compound of formula (I) is not .

[0425] In some embodiments, L is

[0426] wherein: 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, a straight-chain or branched-chain C 1-6 alkyl, or a straight-chain or branched-chain C 1-6 alkoxy; and is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle.

[0427] In some embodiments, L is

[0428] wherein: is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle; Y is -NR 6 - or -O-; R 6 is H, a straight-chain or branched-chain C 1-6 alkyl, or a straight-chain or branched-chain C 1-6 alkoxy; and is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycle.

[0429] In some embodiments, L is

[0430] wherein: is piperidinyl or morpholinyl; Y is -NR 6 - or -O-; R 6 is or ; is cyclobutyl; and Z is -O-.

[0431] In some embodiments, L is

[0432] wherein: is a piperidinyl or a morpholinyl; and is a piperazinyl.

[0433] In some embodiments, is a piperidinyl.

[0434] In some embodiments, the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0435] (Ib), wherein all variables are as defined herein.

[0436] In some embodiments, the compound is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0437] (Ic), wherein all variables are as defined herein.

[0438] In some embodiments, Q 1 -Q 5 are each CR 1 . In some embodiments, 1 - 3 of Q 1 -Q 5 are N. In some embodiments, exactly 1 of Q 1 -Q 5 is N. In some embodiments, exactly 2 of Q 1 -Q 5 are N. In some embodiments, exactly 3 of Q 1 -Q 5 are N.

[0439] In some embodiments, Q 6 -Q 10 are each CR 1 . In some embodiments, 1 - 3 of Q 6 -Q 10 are N. In some embodiments, exactly 1 of Q 6 -Q 10 is N. In some embodiments, exactly 2 of Q 6 -Q 10 are N. In some embodiments, exactly 3 of Q 6 -Q 10 are N.

[0440] In some embodiments, Q 1 is CH, Q2 is C(CH3), Q 3 is C(CN), Q 4 is C(CH3), and Q 5 is CH.

[0441] In some embodiments, Q 1 is CH, Q 2 is C(OCH3), Q 3 is C(CN), Q 4 is CH, and Q 5 is CH.

[0442] In some embodiments, Q 1 is CH, Q 2 is C(Cl), Q 3 is C(CN), Q 4 is CH, and Q 5 is CH.

[0443] In some embodiments, R 1 is selected from the group consisting of: H, CN, and CH3. In some embodiments, R 1 is selected from the group consisting of: 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 R1 is CF3.

[0444] In some embodiments, is a 4- to 6-membered cycloalkyl. In some embodiments, is cyclobutyl or cyclohexyl. In some embodiments, is cyclobutyl. In some embodiments, is cyclopentyl. In some embodiments, is cyclohexyl.

[0445] 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.

[0446] 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 2is 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, R 2 is pentyl. In some embodiments, R 2 is hexyl.

[0447] In some embodiments, is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some embodiments, is phenyl. In some embodiments, is pyridyl. In some embodiments, is pyridazinyl. In some embodiments, is pyrimidinyl. In some embodiments, is pyrazinyl.

[0448] 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.

[0449] 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.

[0450] In one aspect, the present application relates to a compound of formula (Id) or a pharmaceutically acceptable salt thereof:

[0451] (Id), wherein all variables are as defined herein.

[0452] In one aspect, the present application relates to a compound of formula (Ie) or a pharmaceutically acceptable salt thereof:

[0453] (Ie), wherein all variables are as defined herein.

[0454] In one aspect, the present application relates to a compound of formula (If) or a pharmaceutically acceptable salt thereof:

[0455] (If), wherein all variables are as defined herein.

[0456] In one aspect, the present application relates to a compound of formula (Ig) or a pharmaceutically acceptable salt thereof:

[0457] (Ig), wherein all variables are as defined herein.

[0458] In one aspect, the present application relates to a compound of formula (Ih) or a pharmaceutically acceptable salt thereof:

[0459] (Ih), wherein all variables are as defined herein.

[0460] In one aspect, the present application relates to a compound of formula (Ii) or a pharmaceutically acceptable salt thereof:

[0461] (Ii), wherein all variables are as defined herein.

[0462] In one aspect, the present application relates to a compound of formula (Ij) or a pharmaceutically acceptable salt thereof:

[0463] (Ij), wherein all variables are as defined herein.

[0464] In one aspect, the present application relates to a compound of formula (Ik) or a pharmaceutically acceptable salt thereof:

[0465] (Ik), wherein all variables are as defined herein.

[0466] In one aspect, the present application relates to a compound of formula (Il) or a pharmaceutically acceptable salt thereof:

[0467] (Il), wherein all variables are as defined herein.

[0468] In one aspect, the present application relates to a compound of formula (Im) or a pharmaceutically acceptable salt thereof:

[0469] (Im), All variables are as defined herein.

[0470] In one aspect, the present application relates to a compound of formula (Io) or a pharmaceutically acceptable salt thereof:

[0471] (In), All variables are as defined herein.

[0472] In one aspect, the present application relates to a compound of formula (Ip) or a pharmaceutically acceptable salt thereof:

[0473] (Io), All variables are as defined herein.

[0474] In one aspect, the present application relates to a compound of formula (Iq) or a pharmaceutically acceptable salt thereof:

[0475] (Ip), All variables are as defined herein.

[0476] In one aspect, the present application relates to a compound of formula (Ir) or a pharmaceutically acceptable salt thereof:

[0477] (Iq), All variables are as defined herein.

[0478] In one aspect, the present application relates to a compound of formula (Is) or a pharmaceutically acceptable salt thereof:

[0479] (Ir), All variables are as defined herein.

[0480] In some embodiments, the compound of the present disclosure is Compound A, namely: 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, which has the following structure: .

[0481] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for the preparation and functional group transformation and manipulation of organic molecules, including the use of protecting groups, as can be learned from relevant scientific literature or standard reference textbooks in the art according to the present disclosure. Although not limited to any one or several sources, recognized reference textbooks on organic synthesis include: Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition; John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd Edition; John Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2018 / 0099940 and International Publication No. 2018 / 144649 are incorporated herein by reference in their entirety.

[0482] In some embodiments, the compounds of the present disclosure can be prepared according to the procedures and methods disclosed herein, including, for example, as indicated in Table 1. Other bifunctional compounds of the present disclosure can be prepared from common intermediates or their derivatives using similar methods.

[0483] Method for ubiquitinating / degrading a target protein in a cell

[0484] The present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. The method includes administering a bifunctional composition that includes an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked by a linker moiety as further described herein, wherein the E3 ubiquitin ligase binding moiety is conjugated to the protein targeting moiety, and wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein targeting moiety recognizes a target protein such that degradation of the target protein will occur when the target protein is placed near the ubiquitin ligase, resulting in degradation / inhibition of the effect on the target protein and control of the protein level. The control of the protein level provided by the present disclosure provides a treatment for a disease state or disorder that utilizes the regulation of the target protein by reducing the level of the protein in a patient's cells.

[0485] On the one hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, 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 a mutant form of AR.

[0486] As understood by those skilled in the art, AR has a modular structure comprising three functional domains: an N-terminal transcriptional regulatory domain, a DNA-binding domain, and a 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 by a hinge. The AR ligand-binding domain refers to the functional domain of human AR that folds to form a hydrophobic pocket for binding to an AR cognate hormone ligand such as an androgen.

[0487] In addition, it should be understood in the art that AR is 920 amino acid residues in length, wherein the N-terminal transcriptional regulatory domain extends from amino acid residue 1 to approximately amino acid residue 559, the DNA-binding domain extends from approximately amino acid residue 560 to approximately amino acid residue 624, the hinge extends from approximately amino acid residue 625 to approximately amino acid residue 676, and the ligand-binding domain extends from approximately amino acid residue 677 to approximately amino acid residue 920. A suitable AR reference sequence is shown by SEQ ID NO: 1 and is identified as P10275 (ANDR_HUMAN) in the UniProt database. The gene encoding AR (“AR gene”) is approximately 90 kb and has chromosomal coordinates 67544021-67730619 according to the human reference genome GRCh38.p13. The AR gene contains 8 exons, wherein 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).

[0488] In some embodiments, the subject has prostate cancer and contains 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 AR functional domain 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 AR functional domain 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 AR ligand-binding domain 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 AR ligand-binding domain 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 shown 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 shown by SEQ ID NO: 1.

[0489] In some embodiments, an alteration (e.g., substitution) of an amino acid residue in the AR ligand-binding domain provides a mutant AR with reduced ligand specificity and / or enhanced cofactor recruitment. Without being bound by theory, a mutant AR with reduced ligand specificity and / or enhanced cofactor recruitment has increased potency to trigger the AR signaling pathway, thereby conferring a growth advantage on tumor cells containing the mutant AR.

[0490] 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, harvesting the biological sample to obtain genetic material (e.g., genomic DNA or RNA), and performing sequencing analysis, RNA sequencing analysis, or real-time polymerase chain reaction (RT-PCR). For example, in some embodiments, genomic DNA is first obtained (using any standard technique) from cancerous tissue obtained from a subject, cDNA is prepared, and amplification (e.g., using polymerase chain reaction) is performed to provide sufficient cDNA for sequence analysis, and sequencing is performed using, for example, next-generation sequencing. Genomic DNA or RNA is typically extracted from a biological sample (e.g., tissue removed from a subject via, for example, a tissue biopsy). In some embodiments, the biological sample is a tissue biopsy sample (e.g., a prostate biopsy sample) in which sequence analysis of genomic DNA or RNA is performed to identify the presence of somatic mutations in AR (e.g., somatic mutations that result in substitution of amino acid residues in the AR ligand-binding domain). In some embodiments, a biological sample comprising plasma obtained from a subject is used to detect the presence of somatic AR tumor mutations in circulating tumor DNA, e.g., using PCR-based amplification followed by gene sequencing.

[0491] In some embodiments, the AR mutant form degraded by the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises at least one AR somatic tumor mutation.

[0492] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: 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 the following: L702X, V716X, V731X, W742X, M750X, H875X, F877X, T878X, D880X, L882X, S889X, D891X, M895X, M896X, and E898X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is 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).

[0493] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: 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 the following: 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 and is 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).

[0494] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: L702X, T878X, and H875X, wherein "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 the following: 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).

[0495] In some embodiments, the at least one somatic AR tumor mutation is L702X, wherein "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, 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). In some embodiments, the at least one somatic AR tumor mutation is L702H.

[0496] 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 and is 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 and is 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.

[0497] 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 and is 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.

[0498] In some embodiments, the at least one somatic AR tumor mutation is not selected from any one or any combination of the following: 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 the following: L702X, T878X, and H875X, where "X" refers to an amino acid residue other than the wild-type residue at that position, and is 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).

[0499] 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, and is 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.

[0500] In some embodiments, the at least one somatic AR tumor mutation is not 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 not T878X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is 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 and is 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.

[0501] 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 and is 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.

[0502] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: L702H, V716M, V731M, W742L, W742C, H875Y, H875Q, H875L, F877L, T878A, T878S, D880E, L882I, S889G, D891H, D891Y, M896T, M896V, and E898G.

[0503] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: 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 the following: 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 the following: E666K, Q799E, Q793E, Q118K, Y447N, S532Y, G751C, Q825E, T878A, H875Y, H875L, Q825E, W742C, W742L, F877L, T878S, V716M, D891H, M750V, M750T, and S889G.

[0504] In some embodiments, the at least one somatic AR tumor mutation is selected from any one or any combination of the following: 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 the following: 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 the following: 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.

[0505] 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.

[0506] 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.

[0507] In some embodiments, the AR mutant forms degraded by the compound of formula (I) or a pharmaceutically acceptable salt thereof comprise at least two AR somatic tumor mutations.

[0508] 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.

[0509] In some embodiments, the AR mutant forms degraded by the compound of formula (I) comprise at least two AR somatic tumor mutations.

[0510] 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 and is 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).

[0511] 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, where "X" refers to an amino acid residue other than the wild-type residue at that position and is 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).

[0512] 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 and is 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).

[0513] 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.

[0514] 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.

[0515] 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.

[0516] In some embodiments, the at least two somatic AR tumor mutations are selected from L702H, H875Y, T878A, F877L, V716M, T878S, W742C, and W742L.

[0517] In some embodiments, the at least two somatic AR tumor mutations are selected from the following groups 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.

[0518] In some embodiments, the at least two somatic AR tumor mutations are selected from the following groups 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.

[0519] In some embodiments, the at least two somatic AR tumor mutations are selected from the following groups 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.

[0520] In some embodiments, the somatic AR tumor mutations are selected from the following groups of mutations: 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.

[0521] In some embodiments, the somatic AR tumor mutation is not selected from one of the following groups of mutations: 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.

[0522] In some embodiments, the somatic AR tumor mutation is a missense mutation in the AR ligand-binding domain (LBD) and is not selected from one of the following groups of mutations: 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.

[0523] In some embodiments, the present disclosure is directed to a method of treating a disease state or disorder in a patient in need thereof, wherein the disease state or disorder is regulated by a protein and degradation of the protein will produce a therapeutic effect in the patient, the method comprising administering to the 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 disorder may be a disease caused by a microbial agent or other exogenous agent (such as a virus, bacterium, fungus, protozoan or other microbe), or may be a disease state caused by protein overexpression, the overexpression leading to the disease state and / or disorder.

[0524] Treatment method

[0525] 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.

[0526] In one aspect, the present application relates to a method of 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.

[0527] In one aspect, the present application relates to a method of 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.

[0528] In one aspect, the present application relates to a method of 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.

[0529] In one aspect, the present application relates to a method of 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.

[0530] In one aspect, the present application relates to a method of 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.

[0531] The methods for treating cancer described herein result in a reduction in tumor size. Alternatively or additionally, the cancer is metastatic cancer, and the treatment method includes inhibiting the invasion of metastatic cancer cells.

[0532] In some embodiments, the cancer is prostate cancer.

[0533] In some embodiments, the cancer is prostate adenocarcinoma.

[0534] In some embodiments, the cancer is metastatic prostate cancer.

[0535] In some embodiments, the cancer is castration-resistant prostate cancer.

[0536] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0537] In some embodiments, the cancer is progressive mCRPC.

[0538] In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0539] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0540] In some embodiments, the prostate cancer is prostate cancer that has not been treated with novel hormonal agents (NHA).

[0541] In some embodiments, the prostate cancer is metastatic prostate cancer that has not been treated with novel hormonal agents (NHA).

[0542] In some embodiments, the prostate cancer is castration-resistant prostate cancer that has not been treated with novel hormonal agents (NHA).

[0543] In some embodiments, the prostate cancer is castration-sensitive prostate cancer that has not been treated with novel hormonal agents (NHA).

[0544] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that has not been treated with novel hormonal agents (NHA).

[0545] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer that has not been treated with novel hormonal agents (NHA).

[0546] In some embodiments, the prostate cancer is not prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the prostate cancer that is not prostate cancer that has not been treated with a novel hormonal agent (NHA) is also metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0547] In some embodiments, the subject has histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate.

[0548] In some embodiments, the subject with prostate cancer (e.g., mCRPC) is also receiving androgen deprivation therapy (ADT). In some embodiments, ADT includes administering a gonadotropin-releasing hormone analogue or inhibitor to the subject. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is leuprolide, goserelin, triptorelin, histrelin, leuprolide mesylate, or a pharmaceutically acceptable salt thereof. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is leuprolide. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is leuprolide mesylate. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is goserelin. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is goserelin acetate. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is triptorelin. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is triptorelin acetate. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is triptorelin pamoate. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is histrelin. In some embodiments, the gonadotropin-releasing hormone analogue or inhibitor is histrelin acetate. In some embodiments, the subject has had an orchiectomy.

[0549] In some embodiments, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure, the subject experienced progression of prostate cancer during at least one previously approved systemic therapy for metastatic prostate cancer. In some embodiments, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure, the subject experienced progression of prostate cancer during at least two previously approved systemic therapies for metastatic prostate cancer. 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, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure, the subject experienced progression of prostate cancer during at least two previously approved systemic therapies for metastatic prostate cancer, and at least one of the systemic therapies 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.

[0550] In some embodiments, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure, the subject received at least one but no more than three previous second-generation antiandrogens (e.g., enzalutamide, abiraterone acetate, abiraterone, darolutamide, or apalutamide). In some embodiments, the subject received one previous second-generation antiandrogen. In some embodiments, the subject received two previous second-generation antiandrogens. In some embodiments, the subject received three previous second-generation antiandrogens.

[0551] In some embodiments, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure, the subject received no more than two previous chemotherapy regimens. In some embodiments, the subject received two previous chemotherapy regimens. In some embodiments, the subject received one previous chemotherapy regimen. In some embodiments, the subject has not received a previous chemotherapy regimen.

[0552] In some embodiments, prior to administering a therapeutically effective amount of a bifunctional compound of the present disclosure (preferably, Compound A) to treat prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the subject has received no more than two prior chemotherapy regimens. In some embodiments, the subject has received two prior chemotherapy regimens. In some embodiments, the subject has received one prior chemotherapy regimen. In some embodiments, the subject has not received a prior chemotherapy regimen.

[0553] 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.

[0554] In some embodiments, the subject does not have symptomatic brain metastases that require steroids at a dose higher than physiological replacement.

[0555] In some embodiments, the subject does not have active inflammatory bowel disease.

[0556] In some embodiments, the subject does not have chronic diarrhea.

[0557] In some embodiments, the subject does not have diverticulosis.

[0558] In some embodiments, the subject has not previously undergone gastrectomy.

[0559] In some embodiments, the subject has not previously undergone gastric banding surgery.

[0560] In some embodiments, the subject has not received radiotherapy within four weeks prior to the initial administration of a compound of the present disclosure.

[0561] In some embodiments, the subject has not received radiotherapy in which more than about 25% of the patient's bone marrow was irradiated.

[0562] In some embodiments, the subject has not been administered a study drug within four weeks prior to the initial administration of a compound of the present disclosure.

[0563] In some embodiments, the subject has not received a 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 a systemic anti-cancer therapy within two weeks of the first administration of a therapeutically effective amount of a bifunctional compound of the present disclosure, except for an agent that maintains a castrate state.

[0564] In some embodiments, the subject has not received bicalutamide within 6 weeks of the first administration of a therapeutically effective amount of the bifunctional compound of the present disclosure.

[0565] In some embodiments, the subject has not received mitomycin C within 6 weeks of the first administration of a therapeutically effective amount of the bifunctional compound of the present disclosure.

[0566] In some embodiments, the subject has not received nitrosourea within 6 weeks of the first administration of a therapeutically effective amount of the bifunctional compound of the present disclosure.

[0567] 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 the bifunctional compound of the present disclosure.

[0568] In some embodiments, a subject having prostate cancer (e.g., mCRPC) will have a different response 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 in AR.

[0569] In some embodiments, the subject having prostate cancer comprises at least one somatic AR tumor mutation.

[0570] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation L702.

[0571] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation L702H.

[0572] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation M895.

[0573] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation M895V.

[0574] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation W742.

[0575] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation W742C.

[0576] In some embodiments, the subject having prostate cancer comprises at least the somatic AR tumor mutation S889.

[0577] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation S889G.

[0578] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation M750.

[0579] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation M750V.

[0580] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation M896.

[0581] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation M896V.

[0582] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation T878.

[0583] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation T878A.

[0584] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation T878S.

[0585] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation F877.

[0586] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation F877L.

[0587] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation D891.

[0588] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation D891H.

[0589] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation H875.

[0590] In some embodiments, the subject with prostate cancer comprises at least the somatic AR tumor mutation H875Y.

[0591] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations.

[0592] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, T878A / D891H.

[0593] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, T878A / S889G.

[0594] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, F877L / T878A.

[0595] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, L702H and T878A.

[0596] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations, L702H and T878A.

[0597] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, L702H and T878S.

[0598] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations, L702H and T878S.

[0599] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, L702H and H875Y.

[0600] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations, L702H and H875Y.

[0601] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, T878A and H875Y.

[0602] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations, T878A and H875Y.

[0603] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations, T878S and H875Y.

[0604] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations, T878S and H875Y.

[0605] In some embodiments, the subject with prostate cancer comprises at least three somatic AR tumor mutations, L702H, T878A, and H875Y.

[0606] In some embodiments, the subject with prostate cancer comprises three somatic AR tumor mutations, L702H, T878A, and H875Y.

[0607] In some embodiments, the subject with prostate cancer comprises at least three somatic AR tumor mutations, L702H, T878S, and H875Y.

[0608] In some embodiments, the subject with prostate cancer comprises three somatic AR tumor mutations, L702H, T878S, and H875Y.

[0609] In some embodiments, the subject with prostate cancer comprises at least one somatic AR tumor mutation that is not L702H, T878A, T878S, or H875Y.

[0610] In some embodiments, the subject with prostate cancer comprises one somatic AR tumor mutation that is not L702H, T878A, T878S, or H875Y.

[0611] In some embodiments, the subject with prostate cancer comprises at least two somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0612] In some embodiments, the subject with prostate cancer comprises two somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0613] In some embodiments, the subject with prostate cancer comprises at least three somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0614] In some embodiments, the subject with prostate cancer comprises three somatic AR tumor mutations that are not L702H, T878A, T878S, or H875Y.

[0615] On the one hand, the present application relates to the treatment of prostate cancer with a combination of a compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is prostate adenocarcinoma. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic prostate cancer. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-resistant prostate cancer. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castrate-resistant prostate cancer. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is progressive mCRPC. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-sensitive prostate cancer. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castrate-sensitive prostate cancer. In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the prostate cancer treated with the combination of the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castrate-resistant prostate cancer that has not been treated with a novel hormonal agent (NHA).In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castration-sensitive prostate cancer that has not been treated with a novel hormonal agent (NHA). In some embodiments, the other anti-cancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zoledronate, or a pharmaceutically acceptable salt thereof. In some embodiments, the other anti-cancer agent is abiraterone or a pharmaceutically acceptable salt thereof. In some embodiments, the other anti-cancer agent is abiraterone acetate or a pharmaceutically acceptable salt thereof. In some embodiments, the other anti-cancer agent is abiraterone acetate.

[0616] In some embodiments, the present application relates to treating prostate cancer with a combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and 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.

[0617] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is prostate adenocarcinoma, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0618] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic prostate cancer, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0619] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-resistant prostate cancer, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0620] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castration-resistant prostate cancer, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0621] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is progressive mCRPC, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0622] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is castrate-sensitive prostate cancer, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0623] In some embodiments, the prostate cancer treated with the combination of a compound of the present disclosure (preferably, Compound A or a pharmaceutically acceptable salt thereof) and another anti-cancer agent is metastatic castrate-sensitive prostate cancer, wherein the subject has not previously been administered a novel hormonal agent (NHA).

[0624] In some embodiments, the another anti-cancer agent is abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zoledronate or a pharmaceutically acceptable salt thereof.

[0625] In some embodiments, the another anti-cancer agent is abiraterone or a pharmaceutically acceptable salt thereof.

[0626] In some embodiments, the another anti-cancer agent is abiraterone acetate or a pharmaceutically acceptable salt thereof.

[0627] In some embodiments, the another anti-cancer agent is abiraterone acetate.

[0628] On the one hand, treating cancer results in a reduction in tumor size. The reduction in tumor size may also be referred to as "tumor regression". Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment; more preferably, the tumor size is reduced by 10% or more; more preferably, 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. The tumor size can be measured by any reproducible measurement means. In a preferred aspect, the tumor size can be measured as the diameter of the tumor.

[0629] On the other hand, treating cancer results in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its volume before treatment; more preferably, the tumor volume 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. The tumor volume can be measured by any reproducible measurement means.

[0630] On the other hand, treating cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to the number before treatment; more preferably, the number of tumors is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measurement means. In a preferred aspect, the number of tumors can be measured by counting the tumors visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0631] On the other hand, treating cancer results in a reduction in the number of metastatic lesions in other tissues or organs away from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement means. In a preferred aspect, the number of metastatic lesions can be measured by counting the metastatic lesions visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0632] On the other hand, treating cancer results in an increase in the average survival time of the treated subject population compared to the population receiving only the vehicle. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the average survival time of the population can be measured by any reproducible means. In a preferred aspect, the increase in the average survival time of the population can be measured, for example, by calculating the average survival duration of the population after starting treatment with the active agent or compound of the present disclosure. In another preferred aspect, the increase in the average survival time of the population can also be measured, for example, by calculating the average survival duration of the population after completing the first round of treatment with the active agent or compound of the present disclosure.

[0633] On the other hand, treating cancer results in an increase in the average survival time of the treated subject population compared to the untreated subject population. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the average survival time of the population can be measured by any reproducible means. In a preferred aspect, the increase in the average survival time of the population can be measured by calculating the average survival duration of the population after starting treatment with the active agent or compound of the present disclosure. In another preferred aspect, the increase in the average survival time of the population can be measured by calculating the average survival duration of the population after completing the first round of treatment with the compound of the present disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof).

[0634] On the other hand, treating cancer results in a decrease in the tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% relative to the growth rate before treatment; more preferably, the tumor growth rate is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The tumor growth rate can be measured by any reproducible measurement means. In a preferred aspect, the tumor growth rate is measured based on the change in tumor diameter per unit time.

[0635] On the other hand, treating cancer results in a reduction in tumor regrowth. Preferably, after treatment, the tumor regrowth is less than 5%; more preferably, the 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 measurement means. In a preferred aspect, tumor regrowth is measured by measuring the increase in tumor diameter after a prior tumor shrinkage that occurs after treatment. In another preferred aspect, the reduction in tumor regrowth is manifested as the tumor no longer occurring after treatment is stopped.

[0636] In some embodiments, the subject has also been administered a gastric acid modulating agent, a PPI, or an H2 compound. In some embodiments, the subject starts, continues, or maintains the same level of gastric acid modulator treatment while being treated with a compound of formula (I) (e.g., compound A).

[0637] In some embodiments, the subject should not start, continue, or maintain the same level of gastric acid modulator treatment while being treated with a compound of formula (I) (e.g., compound A). In some embodiments, the gastric acid modulator is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid modulator is an H2 compound. In some embodiments, the gastric acid modulator is an antacid.

[0638] In some embodiments, the subject should stop gastric acid regulator therapy or use starting at a certain time point before starting the administration of the 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 regulator is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid regulator is an H2 compound. In some embodiments, the gastric acid regulator is an antacid.

[0639] In some embodiments, the subject should start reducing the level of gastric acid regulator treatment or use at a certain time point before starting the administration of the 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 regulator is a PPI. In some embodiments, the PPI is esomeprazole. In some embodiments, the gastric acid regulator is an H2 compound. In some embodiments, the gastric acid regulator is an antacid.

[0640] In some embodiments, while the subject is being treated with the compound of formula (I) (e.g., compound A), the subject should not start, continue, or maintain the same level of PPI or H2 compound treatment. In some embodiments, the PPI is esomeprazole.

[0641] In some embodiments, while the subject is being treated with the compound of formula (I) (e.g., compound A), the subject should not start, continue, or maintain the same level of PPI treatment. In some embodiments, the PPI is esomeprazole.

[0642] In some embodiments, while the subject is being treated with compound A, the subject should not start, continue, or maintain the same level of esomeprazole treatment.

[0643] In some embodiments, the present invention provides a packaged dosage form of the compound of formula (I) (e.g., compound A) having printed instructions to avoid, reduce, or discontinue the administration or use of a PPI or H2 compound before the administration or use of the compound of formula (I) (e.g., compound A). In some embodiments, the PPI is esomeprazole.

[0644] In some embodiments, the present invention provides a packaged dosage form of Compound A, which has printed instructions to avoid, reduce, or discontinue the administration or use of a PPI before the administration or use of Compound A. In some embodiments, the PPI is esomeprazole.

[0645] A positive food effect has been observed in humans who are administering or using Compound A. For example, compared to humans who have not consumed a high-fat meal before the administration or use of Compound A, consuming a high-fat meal before the administration or use of Compound A has increased the observed C of Compound A max by approximately 4-fold and significantly increased the systemic exposure by approximately 3-fold. In some embodiments, Compound A is orally administered or used with food, i.e., the subject is in a fed state.

[0646] In some embodiments, concomitant use of a PPI with Compound A should be avoided.

[0647] In some embodiments, if PPI treatment or use is needed and no alternative is available, Compound A is orally administered or used with food, i.e., the subject is in a fed state. For example, it is recommended to consume a medium-fat meal (400 to 800 calories, approximately 35% fat) before the administration or use of Compound A.

[0648] In some embodiments, H2 blockers (e.g., cimetidine, famotidine) or topical antacids (e.g., aluminum hydroxide, calcium carbonate, bismuth subsalicylate) can be used. In some embodiments, Compound A is administered or used ≥2 hours before or 10 to 12 hours after the administration or use of an H2 blocker. In some embodiments, Compound A is administered or used ≥2 hours before or after the administration or use of an antacid.

[0649] For any of the methods and uses described herein, the dosage of the compounds of the present disclosure varies depending on factors such as the agent, the age, weight, and clinical condition of the recipient, as well as the experience and judgment of the clinician or practitioner administering the therapy, and other factors that influence the selected dosage.

[0650] A therapeutically effective amount of the compounds of the present disclosure can be administered one or more times per day for up to 30 days or more, followed by 1 day or more without administering the compound. This type of treatment regimen (i.e., administering the compounds of the present disclosure for several consecutive days, followed by several consecutive days without administering the compound) can be referred to as a treatment cycle. The treatment cycle can be repeated as needed multiple times to achieve the desired effect.

[0651] In some embodiments, a therapeutically effective amount of the compounds of the present 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, 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 times, four times or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 consecutive days, or administered once, twice, three times, four times or more times daily, in single or divided doses, for 2 months, 3 months, 4 months, 5 months, 6 months or longer.

[0652] In some embodiments, a therapeutically effective amount of the compounds 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 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg or about 970 to about 1,000 mg, administered once, twice, three times, four times or more times daily, in a single or divided dose (the dose may be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and / or age (years)).

[0653] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 5 mg to about 250 mg.

[0654] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 250 mg to about 500 mg.

[0655] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 500 mg to about 750 mg.

[0656] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 70 mg to about 1000 mg, administered once, twice, three times, four times or more times daily, in a single or divided dose (the dose may be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and / or age (years)).

[0657] In some embodiments, a therapeutically effective amount of the compounds of the present 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 times or more times daily, in a single or divided dose (the dose may be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and / or age (years)).

[0658] In some embodiments, a therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

[0659] In some embodiments, a therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

[0660] In some embodiments, a therapeutically effective amount of Compound A is from about 10 mg to about 500 mg.

[0661] In some embodiments, a therapeutically effective amount of Compound A is from about 20 mg to about 250 mg.

[0662] In some embodiments, a therapeutically effective amount of Compound A is from about 100 mg to about 500 mg.

[0663] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 100 mg, about 150 mg, or about 300 mg.

[0664] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 100 mg.

[0665] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 100 mg.

[0666] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 100 mg, administered orally once daily.

[0667] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 150 mg.

[0668] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 150 mg.

[0669] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 150 mg, administered orally once daily.

[0670] In some embodiments, a therapeutically effective amount of Compound A is about 200 mg.

[0671] In some embodiments, a therapeutically effective amount of Compound A is 200 mg.

[0672] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 150 mg, administered orally once daily.

[0673] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 300 mg.

[0674] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 300 mg.

[0675] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 300 mg, administered orally once daily.

[0676] In some embodiments, a therapeutically effective amount of Compound A is about 320 mg.

[0677] In some embodiments, a therapeutically effective amount of Compound A is 320 mg.

[0678] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 320 mg, administered orally once daily.

[0679] In some embodiments, a therapeutically effective amount of Compound A is about 400 mg.

[0680] In some embodiments, a therapeutically effective amount of Compound A is 400 mg.

[0681] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 400 mg, administered orally once daily.

[0682] In some embodiments, a therapeutically effective amount of Compound A is about 480 mg.

[0683] In some embodiments, a therapeutically effective amount of Compound A is 480 mg.

[0684] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 480 mg, administered orally once daily.

[0685] In some embodiments, a therapeutically effective amount of Compound A is about 500 mg.

[0686] In some embodiments, a therapeutically effective amount of Compound A is 500 mg.

[0687] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is 500 mg, administered orally once daily.

[0688] The therapeutically effective amount of the compounds of the present disclosure can also be in the range of from about 0.01 mg / kg / day to about 100 mg / kg / day. In one aspect, the therapeutically effective amount of the compounds of the present disclosure can be in the range of from about 0.05 mg / kg / day to about 10 mg / kg / day. In one aspect, the therapeutically effective amount of the compounds of the present disclosure can be in the range of from about 0.075 mg / kg / day to about 5 mg / kg / day. In one aspect, the therapeutically effective amount of the compounds of the present disclosure can be in the range of from about 0.10 mg / kg / day to about 1 mg / kg / day. In one aspect, the therapeutically effective amount of the compounds of the present disclosure can be in the range of from about 0.20 mg / kg / day to about 0.70 mg / kg / day.

[0689] In some embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.10 mg / kg / day, about 0.15 mg / kg / day, about 0.20 mg / kg / day, about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day or about 1.00 mg / kg / day.

[0690] In some embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 1.05 mg / kg / day, about 1.10 mg / kg / day, about 1.15 mg / kg / day, about 1.20 mg / kg / day, about 1.25 mg / kg / day, about 1.30 mg / kg / day, about 1.35 mg / kg / day, about 1.40 mg / kg / day, about 1.45 mg / kg / day, about 1.50 mg / kg / day, about 1.55 mg / kg / day, about 1.60 mg / kg / day, about 1.65 mg / kg / day, about 1.70 mg / kg / day, about 1.75 mg / kg / day, about 1.80 mg / kg / day, about 1.85 mg / kg / day, about 1.90 mg / kg / day, about 1.95 mg / kg / day or about 2.00 mg / kg / day.

[0691] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is about 2 mg / kg / day, about 2.5 mg / kg / day, about 3 mg / kg / day, about 3.5 mg / kg / day, about 4 mg / kg / day, about 4.5 mg / kg / day, about 5 mg / kg / day, about 5.5 mg / kg / day, about 6 mg / kg / day, about 6.5 mg / kg / day, about 7 mg / kg / day, about 7.5 mg / kg / day, about 8.0 mg / kg / day, about 8.5 mg / kg / day, about 9.0 mg / kg / day, about 9.5 mg / kg / day, or about 10 mg / kg / day.

[0692] In some embodiments, a therapeutically effective amount of the compounds of the present disclosure is administered to a subject once daily. In some embodiments, such daily dose of the compounds of the present disclosure can be administered to the subject as a single dose. In some embodiments, such daily dose of the compounds of the present disclosure can be divided into two portions (i.e., divided doses) and administered to the subject. In some embodiments, such daily dose of the compounds of the present disclosure can be administered to the subject in three divided doses. In some embodiments, such daily dose of the compounds of the present disclosure can be administered to the subject in four divided doses. In some embodiments, such daily dose of the compounds of the present disclosure can be administered to the subject in five or more divided doses. In some embodiments, these portions or divided doses are administered to the subject at regular time intervals throughout the day, such as every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0693] A therapeutically effective amount of the compounds of the present disclosure can be initially estimated in cell culture assays or in animal models (commonly rats, mice, rabbits, dogs, or pigs). Such animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine the available doses and routes of administration in humans. Therapeutic / preventive efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, and it can be expressed as the ratio LD 50 / ED 50 . Pharmaceutical compositions with a large therapeutic index are preferably exhibited. The dose can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0694] Adjust the dosage and administration to provide an adequate level of the compounds of the present disclosure or to maintain the desired effect. Factors to be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance / response to the therapy. The long-acting pharmaceutical composition may be administered every 3 to 4 days, weekly, bi-weekly or monthly, depending on the half-life and clearance rate of the particular formulation.

[0695] In some embodiments, for a 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 the compound of the present disclosure is described herein, and a 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, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790,795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995 or 1,000 mg, administered once, twice, three times, four times 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 administered once, twice, three times, four times or more times daily, in single or divided doses, for 2 months, 3 months, 4 months, 5 months, 6 months or longer.

[0696] 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 the compound of the present disclosure is described herein, and therapeutically effective amounts of abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate are 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700,705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995 or 1,000 mg, administered once, twice, three times, four times or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 days continuously, or administered once, twice, three times, four times or more times daily, in single or divided doses, for 2 months, 3 months, 4 months, 5 months, 6 months or longer. 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, the therapeutically effective amount of the compound of the present disclosure is described herein, and 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.,

[0697] 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, the therapeutically effective amount of the compound of the present disclosure is described herein, and 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.

[0698] 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, the therapeutically effective amount of the compound of the present disclosure is described herein, and 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.

[0699] 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, the therapeutically effective amount of the compound of the present disclosure is described herein, and 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.

[0700] 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, the therapeutically effective amount of the compound of the present disclosure (preferably, Compound A) is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg, orally administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 days or more, in a single or divided dose. In some embodiments, abiraterone acetate is co-administered with a corticosteroid, orally administered once or twice daily. In some embodiments, abiraterone acetate is co-administered with 5 mg of prednisone or prednisolone, orally administered twice daily.

[0701] 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, the therapeutically effective amount of the compound of the present disclosure (preferably, Compound A) is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg, orally administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 days or more, in a single or divided dose. In some embodiments, abiraterone acetate is co-administered with 5 mg of prednisone, orally administered twice daily. In some embodiments, the combination of the compound of the present disclosure (preferably, Compound A) and abiraterone acetate is administered to a subject in need who is in a fasting state. In some embodiments, the subject does not eat for at least two hours before and at least one hour after administration of the combination of the compound of the present disclosure (preferably, Compound A) and abiraterone acetate.

[0702] In some embodiments, the compound of the present disclosure (preferably, Compound A) and abiraterone acetate are administered to the subject simultaneously. In some embodiments, the compound of the present disclosure (preferably, Compound A) and abiraterone acetate are administered to the subject sequentially.

[0703] In some embodiments, the compounds of the present disclosure (preferably, Compound A) and the anti-cancer agent are administered to the subject in a temporally proximate manner.

[0704] In some embodiments, "temporally proximate" means that the administration of the compounds of the present disclosure occurs within a period of time before or after the administration of the anti-cancer agent such that the therapeutic effect of the compounds of the present disclosure overlaps with the therapeutic effect of the anti-cancer agent. In some embodiments, the therapeutic effect of the compounds of the present disclosure completely overlaps with the therapeutic effect of the anti-cancer agent. In some embodiments, "temporally proximate" means that the administration of the compounds of the present disclosure occurs within a period of time before or after the administration of the anti-cancer agent such that there is a synergistic effect between the compounds of the present disclosure and the anti-cancer agent. In some embodiments, the anti-cancer agent is abiraterone acetate.

[0705] "Temporally proximate" can vary according to 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 to be administered; the disease or disorder to be treated or ameliorated; the therapeutic outcome to be achieved; the dose, dosing frequency, and dosing duration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "temporally proximate" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be carried out in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0706] In some embodiments, the compounds 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 to the subject simultaneously.

[0707] In some embodiments, the compounds 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 to the subject simultaneously in separate formulations (e.g., in separate tablets). In some embodiments, the compounds 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 to the subject simultaneously in the same formulation (e.g., in a single tablet).

[0708] In some embodiments, the compounds 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 sequentially administered to the subject.

[0709] In some embodiments, the compounds 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 to the subject in a time - proximate manner.

[0710] In some embodiments, the compounds of the present disclosure (preferably, Compound A) are administered to the subject before abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate, wherein the subject is in a fasting state.

[0711] In some embodiments, the compounds of the present disclosure (preferably, Compound A) are administered to the subject before abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate, wherein the subject is in a fed state.

[0712] In some embodiments, the compounds of the present disclosure (preferably, Compound A) are administered to the subject after abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate, wherein the subject is in a fasting state.

[0713] In some embodiments, the compounds of the present disclosure (preferably, Compound A) are administered to the subject after abiraterone, a pharmaceutically acceptable salt of abiraterone, abiraterone acetate, or a pharmaceutically acceptable salt of abiraterone acetate, wherein the subject is in a fed state.

[0714] Pharmaceutical composition

[0715] In some embodiments, the compounds of the present disclosure (preferably, Compound A) are formulated for oral administration. For example, in some embodiments, the compounds of the present disclosure (preferably, Compound A) are formulated into tablets that contain zero, one, two, or more of the following: an emulsifier; a surfactant, a binder; a disintegrant, a glidant; and a lubricant.

[0716] In some embodiments, the emulsifier is hypromellose.

[0717] In some embodiments, the surfactant is vitamin E polyethylene glycol succinate.

[0718] In some embodiments, the binder (also referred to herein as filler) is selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0719] In some embodiments, the disintegrant is croscarmellose sodium.

[0720] In some embodiments, the glidant refers to a substance used to promote powder flow by reducing the cohesive force between particles. In some embodiments, in the dosage forms of the present disclosure, the glidant is selected from the group consisting of: silica, colloidal anhydrous silica, starch, and talc.

[0721] In some embodiments, the lubricant refers to a substance that prevents the ingredients from sticking and / or aggregating together in the machine 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.

[0722] The pharmaceutical composition containing the compound of the present disclosure (preferably, compound A) can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, encapsulating, embedding, or lyophilization processes. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which contain excipients and / or adjuvants that facilitate the processing of the compound of the present disclosure into a pharmaceutically usable preparation. Of course, the appropriate formulation depends on the selected route of administration.

[0723] A pharmaceutical composition suitable for injectable use includes a sterile aqueous solution (in the case of water-soluble) or dispersion 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, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy injection is possible. It 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, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents in the composition, such as sugars, polyols (such as mannitol, sorbitol), sodium chloride. The absorption of the injectable composition can be prolonged by including agents that delay absorption (such as aluminum monostearate and gelatin) in the composition.

[0724] A sterile injectable solution can be prepared by incorporating the required amount of the compound of the present disclosure (preferably, Compound A) with one or a combination of the ingredients listed above into a suitable solvent as required, followed by filtration sterilization. Generally, a dispersion is prepared by incorporating the active agent or compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying to produce a powder of the active ingredient plus any additional required ingredients from its previously sterile filtered solution.

[0725] Oral compositions generally include 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 can be combined with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the agent or compound in the fluid carrier is orally applied, swished, and then spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange essence.

[0726] For administration by inhalation, the agent or compound is delivered in the form of an aerosol spray from a pressurized container or dispenser (which contains a suitable propellant, e.g., a gas such as carbon dioxide) or a nebulizer.

[0727] Systemic administration can also be effected by transmucosal or transdermal means. For transmucosal or transdermal administration, permeating agents suitable for the permeation barrier are used in the formulation. Such permeating agents are generally known in the art and include, for example, (for transmucosal administration) detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished by using a nasal spray or a suppository. For transdermal administration, the active agent or compound is formulated into an ointment, paste, gel, or cream generally known in the art.

[0728] In one aspect, the compounds of the present disclosure (preferably, Compound A) are prepared with a pharmaceutically acceptable carrier that will protect the agent or compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulation 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. Liposome suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as a pharmaceutically acceptable carrier. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0729] 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, a unit dosage form refers to a physically discrete unit suitable as a unit dose for a subject to be treated; each unit contains a predetermined quantity of the active agent or compound, the quantity being calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of the unit dosage forms of the present application are determined by and directly depend on the unique characteristics of the compounds disclosed herein and the particular therapeutic effect to be achieved.

[0730] The pharmaceutical composition may be included in a container, package, or dispenser together with instructions for administration.

[0731] Illustrative modes of administration of the compounds disclosed herein (preferably, Compound A) include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. In some embodiments, the compounds disclosed herein are administered orally. In some embodiments, the compounds disclosed herein are administered in the form of tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, or pellets.

[0732] Exemplary pharmaceutical compositions are tablets and gelatin capsules that comprise a salt of a compound of the present disclosure (preferably, Compound A) and a pharmaceutically acceptable carrier, such as a) diluents, e.g., purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) lubricants, e.g., silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural gums and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), waxes, and / or polyvinylpyrrolidone (if necessary); d) disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, coloring agents, flavoring agents, and sweetening agents; f) emulsifying or dispersing agents, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifying agents; and / or g) agents that enhance salt absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200.

[0733] To prepare pharmaceutical compositions from the compounds or salts or hydrates of the present disclosure, the inert, pharmaceutically acceptable carrier can be solid or liquid. Solid form formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets can contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture of various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th ed., (1990), Mack Publishing Co., Easton, Pa.

[0734] Formulations in liquid form include solutions, suspensions, and emulsions. For example, water or water - propylene glycol solutions for parenteral injection, or sweeteners and opacifiers added for oral solutions, suspensions, and emulsions. Liquid - form formulations can also include solutions for intranasal administration.

[0735] Liquid (especially injectable) compositions can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed salts are dissolved in or mixed with a pharmaceutically acceptable solvent such as water, physiological saline, dextrose aqueous solution, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to dissolve the disclosed compounds.

[0736] Parenteral injectable administration is generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms such as liquid solutions or suspensions, or in solid forms suitable for dissolution in a liquid before injection.

[0737] Aerosol formulations suitable for inhalation can include solutions and solids in powder form, which can be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, for example nitrogen.

[0738] Also included are solid - form formulations that are intended to be converted into liquid - form formulations for oral or parenteral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions.

[0739] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi - solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, timed - release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and in accordance with conventional pharmaceutical practice. Similarly, they can be administered intravenously (bolus and infusion), intraperitoneally, intrathecally, subcutaneously, or intramuscularly, and all in forms well - known to those skilled in the pharmaceutical art.

[0740] The pharmaceutical compositions can be prepared according to conventional mixing, granulating, or coating methods respectively, and the pharmaceutical compositions of the present invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% by weight or volume of the disclosed free base or salt.

[0741] The pharmaceutical compositions containing the disclosed compounds (preferably, Compound A) can also contain one or more additional anticancer agents, including any of those disclosed herein.

[0742] Unless otherwise stated, all amounts of any component of the oral dosage forms (e.g., tablets) described herein are indicated as % w / w and refer to the total weight of the oral dosage form.

[0743] Examples

[0744] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure thereby. It should also be understood that various other embodiments, modifications, and equivalent schemes that may be contemplated by those skilled in the art may be made without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0745] Example 1 - Degradation of AR in wild-type LNCaP and VCaP cells

[0746] To determine the pharmacological effects of compound A in vitro, AR degradation assays were performed in VCaP (vertebral metastasis of prostate cancer) cancer cells and LNCaP (lymph node cancer of prostate) cancer cells carrying AR amplification and AR mutation (T878A) mutations, respectively. ( Figure 2 ) After 24-hour treatment, compound A effectively degraded AR in LNCaP (D max ≥91% and DC 50 ≤1.3 nM) and VCaP (D max ≥94% and DC 50 <1 nM). A degradation time-course experiment was also performed in VCaP cells, showing that >50% AR degradation was achieved within 2 hours of compound A treatment of VCaP cells, and almost complete elimination of intracellular AR was observed after 6 hours. Since compound A is thought to engage with cereblon protein at the same binding site as immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, excess pomalidomide would compete for the binding of compound A to cereblon protein. Consistent with the mode of action of PROTACs, pomalidomide (10 μM) blocked compound A-mediated degradation. In addition, a polyubiquitination assay was also performed, showing that compound A treatment significantly increased the ubiquitination of AR. These data support the proposed mode of action of compound A, i.e., degradation of AR through engagement with the E3 ligase cereblon, ubiquitination of AR, and degradation via the proteasome.

[0747] Example 2 - Degradation of AR proteins carrying clinically relevant point mutants

[0748] To evaluate the ability of compound A to degrade AR variants, vectors expressing wild-type AR or mutant AR proteins carrying clinically observed mutations in the ligand-binding domain (either 1 with a single amino acid change or 4 with 2 amino acid changes) (Azad A.A., Volik S.V., Wyatt A.W. 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 E.M., Wu Y.M. et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161:1215-1228; Ledet E.M., Lilly M.B., Sonpavde G. et al. Comprehensive analysis of AR alterations in circulating tumor DNA from patients with advanced prostate cancer. Oncologist. April 2020; 25(4):327-333) were stably transfected into HEK293 or T-REx™-293 cells that do not express endogenous AR (Table 1, Figure 3 and Figure 10 ). Degradation of all clinically relevant AR point mutants tested by compound A was comparable to that observed for wild-type AR.

[0749] Table 1. Half-maximal degradation concentration (DC 50 ) of compound A for wild-type and mutant AR expressed in the T-Rex-293 cell line

[0750] SEM = standard error of the mean.

[0751] The degradation of AR by compound A in all AR variants was characterized by ELISA, except for AR D891H (asterisk), which was characterized by Western blot. For Western blot analysis, the AR levels were quantified by densitometry using Bio-Rad ImageLab software. The AR band intensity was normalized against the corresponding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) band. For wild-type AR and all mutants, the percentage of remaining AR relative to vehicle control was calculated. GraphPad PRISM was used to perform plotting and curve fitting using a four-parameter logistic (4PL) model. Nonlinear fitting was used to calculate the half-maximal degradation concentration (DC 50 ) value.

[0752] Example 3 - In Vitro Evaluation of the Degradation Potential of New Cereblon Substrates

[0753] Treatment of Ramos and SK-N-DZ cells with 1 µM compound A did not result in the degradation of GSPT1, Aiolos, Ikaros, CK1α, and SALL4 ( Figure 4 ). Other PROTAC compound controls (Con A-D), A3370 (a known degrader of nascent substrates), and 10 mM lenalidomide were also tested. Compound A engages the cereblon protein at the same site as IMiDs. As expected, lenalidomide and A3370 induced the degradation of CBN new substrates. Since compound A did not result in the degradation of known cereblon nascent substrates, potential liabilities attributed to the IMiD class (thalidomide, pomalidomide, lenalidomide) may not apply to compound A.

[0754] Example 4 - Inhibition of Prostate Tumor Growth by Compound A in a Complete (Non-Castrated) Mouse VCaP Model

[0755] To mimic the higher androgen levels found in an environment of incomplete testosterone suppression, intact (non-castrated) mice were used for VCaP tumor xenograft studies. Published data on enzalutamide indicate that its activity is very limited or non-existent in the intact VCaP setting (Asangani, I. A., Dommeti, V. L., 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 with oral vehicle, enzalutamide (20 mg / kg, "ENZA") or compound A (10, 3, and 1 mg / kg / day), once daily (QD) for 21 days. As Figure 5 shown, compound A exhibited 98%, 74%, and 34% tumor growth inhibition (TGI) at 10, 3, and 1 mg / kg / day, respectively, while limited efficacy (TGI = 27%) was observed in mice treated with enzalutamide.

[0756] Plasma PSA levels are used as a clinical biomarker of disease progression and are thought to be closely related to the degree of AR...

Claims

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

2. A method for treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

3. A method of treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) A compound A in a therapeutically effective amount, , or a pharmaceutically acceptable salt thereof; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

4. A method of treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) A compound A in a therapeutically effective amount, ; and (ii) 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 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 1-4, wherein the prostate cancer is prostate adenocarcinoma.

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

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

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

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

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

11. A method of treating prostate cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

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

13. A method of treating prostate cancer in a subject, the method comprising administering to the subject in need thereof: (i) A therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; wherein the prostate cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer; and 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 10-13, wherein the prostate cancer is castration-sensitive prostate cancer.

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

16. A method of treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

17. A method of treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

18. A method of treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) A compound A in a therapeutically effective amount, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

19. A method of treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

20. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA is metastatic prostate cancer that has not been treated with NHA.

21. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA is castration-resistant prostate cancer that has not been treated with NHA.

22. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA is castration-sensitive prostate cancer that has not been treated with NHA.

23. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA is metastatic castration-resistant prostate cancer that has not been treated with NHA.

24. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA is metastatic castration-sensitive prostate cancer that has not been treated with NHA.

25. The method according to any one of claims 16-19, wherein the prostate cancer that has not been treated with NHA has not been previously treated with second-generation antiandrogens.

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

27. The method according to any one of claims 16 - 19, wherein the prostate cancer that has not received NHA treatment has not been previously treated with abiraterone acetate.

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

29. The method according to any one of claims 16 - 27, wherein the prostate cancer that has not received NHA treatment has not been previously treated with an anti - cancer agent.

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

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

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

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

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

35. The method according to any one of claims 1 - 33, wherein the therapeutically effective amount of compound A is administered to the subject once a day, twice a day, three times a day, or four times a day.

36. The method according to any one of claims 1 - 35, wherein the therapeutically effective amount of compound A is administered to the subject once a day.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

52. The method according to any one of claims 1-50, wherein the subject with prostate cancer comprises at least one somatic AR tumor mutation.

53. The method according to claim 51 or 52, wherein the at least one somatic AR tumor mutation is an AR ligand-binding domain missense mutation.

54. The method according to any one of claims 51-53, wherein 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" 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).

55. The method according to any one of claims 51-53, 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. The method according to 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 method according to any one of claims 51 - 53, wherein 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. The method according to any one of claims 51 - 57, wherein the at least one somatic AR tumor mutation is L702H.

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

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

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

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

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

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

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

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

70. The method according to any one of claims 1-69, wherein the subject stops using a PPI before starting the administration of compound A or a pharmaceutically acceptable salt thereof.

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

72. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, , 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

73. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of compound A, ； 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

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

75. A method for treating prostate cancer in a subject having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) 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 progressive metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of compound A is from about 5 mg to about 750 mg.

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

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

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

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

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

81. A method of treating a subject with prostate cancer having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

82. A method of treating a subject with prostate cancer having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ； wherein the prostate cancer having at least one somatic AR tumor mutation is castration - sensitive prostate cancer or metastatic castration - sensitive prostate cancer; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

83. A method of treating a subject with prostate cancer having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof: (i) A compound A in a therapeutically effective amount, , or a pharmaceutically acceptable salt thereof; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

84. A method of treating a subject with prostate cancer having at least one somatic AR tumor mutation, the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) 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 wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

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

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

87. A method of treating a subject with prostate cancer having at least one somatic AR tumor mutation who has not received novel hormonal agent (NHA) treatment, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, , or a pharmaceutically acceptable salt thereof; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

88. A method for treating prostate cancer in a subject with at least one somatic AR tumor mutation who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound A, ; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

89. A method for treating prostate cancer in a subject with at least one somatic AR tumor mutation who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) A compound A in a therapeutically effective amount, , or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of Compound A is from about 5 mg to about 750 mg.

90. A method for treating prostate cancer in a subject with at least one somatic AR tumor mutation who has not been treated with a novel hormonal agent (NHA), the method comprising administering to the subject in need thereof: (i) a therapeutically effective amount of Compound A, ; and (ii) a therapeutically effective amount of abiraterone acetate; and wherein the therapeutically effective amount of Compound A is from about 1 mg to about 1000 mg.

91. The method according to any one of claims 87-90, wherein the prostate cancer with at least one somatic AR tumor mutation that has not been treated with NHA is metastatic prostate cancer that has not been treated with NHA.

92. The method according to any one of claims 87-90, wherein the prostate cancer with at least one somatic AR tumor mutation that has not been treated with NHA is castration-resistant prostate cancer that has not been treated with NHA.

93. The method according to any one of claims 87-90, wherein the prostate cancer with at least one somatic AR tumor mutation that has not been treated with NHA is castration-sensitive prostate cancer that has not been treated with NHA.

94. The method according to any one of claims 87-90, wherein the prostate cancer with at least one somatic AR tumor mutation that has not been treated with NHA is metastatic castration-resistant prostate cancer that has not been treated with NHA.

95. The method according to any one of claims 87-90, wherein the prostate cancer with at least one somatic AR tumor mutation that has not been treated with NHA is metastatic castration-sensitive prostate cancer that has not been treated with NHA.

96. The method according to any one of claims 72-95, wherein the at least one somatic AR tumor mutation is an AR ligand-binding domain missense mutation.

97. The method according to any one of claims 72 - 96, wherein 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, where "X" refers to an amino acid residue other than the wild - type residue at the 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).

98. The method according to 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. The method according to 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 method according to any one of claims 72 - 96, wherein 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. The method according to any one of claims 72 - 100, wherein the at least one somatic AR tumor mutation is L702H.

102. A combination preparation: (a) Compound A, or a pharmaceutically acceptable salt thereof; and (b) Abiraterone acetate; for use simultaneously, separately, or sequentially in a method of 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, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer.

103. The combination preparation according to claim 102, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily.

104. The combination preparation according to claim 102 or 103, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily.

105. A combination preparation: (a) compound A, or a pharmaceutically acceptable salt thereof; and (b) abiraterone acetate; for use simultaneously, separately or sequentially in a method of treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA).

106. The combination preparation according to claim 105, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily.

107. The combination preparation according to claim 105 or 106, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily.

108. The combination preparation according to any one of claims 105-107, wherein the prostate cancer that has not received treatment with a novel hormonal agent (NHA) is metastatic prostate cancer that has not received NHA treatment, castration-resistant prostate cancer that has not received NHA treatment, castration-sensitive prostate cancer that has not received NHA treatment, metastatic castration-resistant prostate cancer that has not received NHA treatment or metastatic castration-sensitive prostate cancer that has not received NHA treatment.

109. Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily; wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer.

110. Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily; wherein the prostate cancer is prostate adenocarcinoma, metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, progressive metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer.

111. Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject who has not been treated with a novel hormonal agent (NHA), wherein the method comprises: (i) orally administering about 5 mg to about 750 mg of Compound A or a pharmaceutically acceptable salt thereof once daily; and (ii) orally administering about 250 mg to about 1500 mg of abiraterone acetate once daily.

112. Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject who has not received treatment with a novel hormonal agent (NHA), the method comprising: (i) orally administering about 5 mg to about 750 mg of Compound A once daily; and (ii) orally administering about 1000 mg of abiraterone acetate once daily.

113. The compound for use according to claim 111 or 112, wherein the prostate cancer that has not been treated with a novel hormonal agent (NHA) is metastatic prostate cancer that has not been treated with NHA, castration-resistant prostate cancer that has not been treated with NHA, castration-sensitive prostate cancer that has not been treated with NHA, metastatic castration-resistant prostate cancer that has not been treated with NHA or metastatic castration-sensitive prostate cancer that has not been treated with NHA.

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