Use of androgen receptor degraders in the treatment of spinal and bulbar muscular atrophy

Abstract

This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) or one or more SBMA symptoms, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to a subject in need. Compound A

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Application No. 63 / 608,071, filed December 8, 2023, which is hereby incorporated in its entirety by reference.

[0003] sequence list

[0004] The sequence list XML related to this application is provided electronically in XML format and is hereby incorporated by reference. The XML file containing the sequence list XML is named "ARVN-057_ST26_SeqListing.xml". This XML file is 6,458 bytes long, created on December 3, 2024, and filed electronically via the USPTO Patent Centre. Technical Field

[0005] This disclosure provides methods for treating or preventing spinal bulbar muscular atrophy (SBMA) or one or more SBMA symptoms. Background Technology

[0006] SBMA is a rare, inherited X-linked neuromuscular disease caused by the amplification of CAG repeats at q11-12 of the AR gene (Arnold, FJ et al. 2019, The Journal of the American Society for Experimental NeuroTherapeutics 16, 928-947; Spada, ARL et al. 1991, Nature 352, 77-79). Typically, individuals unaffected by SBMA (i.e., healthy individuals) are expected to have between 5 and 36 CAG repeats in the AR gene, while 38 or more CAG repeats cause SBMA (Chivet, Mathilde et al., “Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism.” Cells Vol. 9, 2 325. January 30, 2020). PolyQ-containing AR proteins with an aggregation tendency (polyQ-AR) drive chronic and progressive neuromuscular symptoms of SBMA through an androgen-dependent toxic gain-of-function mechanism (Yu, Z. et al. 2006, The Journal of Clinical Investigation 116, 2663-2672; Katsuno, M. et al. 2002, Neuron 35, 843-854). In fact, female carriers experience only mild symptoms (Rhodes, LE et al. 2009, A Journal of Neurology 132, 3242-3251). (CAG) nThe frequency of male carriers with ≥38 is estimated to be 27 per 100,000 people, and a recent study estimated the prevalence of the disease to be 1 per 6,887 men (Laskaratos et al. 2021, Méd. Genet. 58, 385-391; Zanovello, M. et al. Brain. 2023 July 3;146(7):2723-2729. doi: 10.1093 / brain / awad050.PMID: 36797998; PMCID: PMC10316764). SBMA patients typically develop symptoms between the ages of 30 and 50 and experience slow, progressive degeneration of muscles and lower motor neurons, manifesting as muscle weakness, atrophy, fasciculations, difficulty walking, and dysphagia (Breza, M. et al. 2019, Journal of Neurology 266, 565-573). Most patients experience difficulty climbing stairs within ten to twenty years of diagnosis; nearly one-third require a wheelchair within twenty years of symptom onset. Severely affected individuals (many of whom are unable to walk) are at risk of aspiration pneumonia and ventilatory failure due to weakness of the medullary and respiratory muscle tissues (Atsuta, N. et al. 2006, Brain 129, 1446-1455).

[0007] Non-clinical models of SBMA demonstrate that muscle cells are severely affected by the disease and are a major driver of motor dysfunction (Cortes, CJ et al. 2014, Neuron 82, 295-307). Several rodent models summarize the muscle weakness observed in patients with SBMA (Yu, Z. et al. 2006, The Journal of Clinical Investigation 116, 2663-2672; Cortes, CJ et al. 2014, Neuron 82, 295-307; Chivet, M. et al. 2020, Cells 9, 325; Badders, NM et al. 2018, Nature Medicine 24, 427-437). PolyQ-AR disrupts Akt and mTOR signaling (Rocci A. et al., Acta Neuropathologica 132, 127-144), metabolic dysfunction (Giorgetti, E. et al., 2016, Cell Rep. 17, 125-136), and the ubiquitin-proteasome system (Nath, SR et al., 2018, The Journal of Clinical Investigation 128, 3630-3641). Reducing polyQ-AR is a promising therapeutic intervention targeting the root cause of the disease (Grunseich, C. et al., 2020, Current Opinion in Neurology 33, 629-634). When polyQ-AR was conditionally knocked out using a muscle-specific Cre recombinase, SBMA-like symptoms disappeared in a BAC transgenic mouse model of SBMA (Cortes, CJ et al., 2014, Neuron 82, 295-307). Furthermore, in knock-in rodent models, peripheral antisense oligonucleotide (ASO)-mediated knockdown of polyQ-AR information improved motor function (Lieberman, AP et al. 2014, Cell reports 7, 774-784). These studies suggest that removing polyQ-AR in muscle is a potential disease-modifying therapy. Conversely, conditional knockout of polyQ-AR in motor neurons did not affect disease progression in BAC transgenic models (Gromova, A. et al. 2023, Acta Neuropathol. Commun. 11, 90). Summary of the Invention

[0008] In one aspect, this application relates to a method of treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0009] Or, or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, this application relates to a method of treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0011] .

[0012] In one respect, this application relates to compound A,

[0013] Or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0014] In one respect, this application relates to compound A,

[0015] The method of using it in treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0016] In one respect, this application relates to compound A,

[0017] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0018] In one respect, this application relates to compound A,

[0019] Use for preparing a medicament for treating spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0020] In one aspect, this application relates to a method of treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0021] Or, or a pharmaceutically acceptable salt thereof.

[0022] In one aspect, this application relates to a method of treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0023] .

[0024] In one respect, this application relates to compound A,

[0025] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0026] In one respect, this application relates to compound A,

[0027] The compound A is used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering about 1 mg to about 500 mg of compound A to the subject.

[0028] In one respect, this application relates to compound A,

[0029] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0030] In one respect, this application relates to compound A,

[0031] Use for preparing a medicament for treating spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A, and the medicament is administered to a subject in need.

[0032] In one aspect, this application relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0033] Or, or a pharmaceutically acceptable salt thereof.

[0034] In one aspect, this application relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0035] .

[0036] In one respect, this application relates to compound A,

[0037] Or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0038] In one respect, this application relates to compound A,

[0039] The method of using it in treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0040] In one respect, this application relates to compound A,

[0041] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0042] In one respect, this application relates to compound A,

[0043] Use for preparing a medicament for treating symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0044] In one aspect, this application relates to a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0045] Or, or a pharmaceutically acceptable salt thereof.

[0046] In one aspect, this application relates to a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0047] .

[0048] In one respect, this application relates to compound A,

[0049] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0050] In one respect, this application relates to compound A,

[0051] The compound A is used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering about 1 mg to about 500 mg of compound A to the subject.

[0052] In one respect, this application relates to compound A,

[0053] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0054] In one respect, this application relates to compound A,

[0055] Use for preparing a medicament for treating symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A, and the medicament is administered to a subject in need.

[0056] In one aspect, this application relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0057] Or, or a pharmaceutically acceptable salt thereof.

[0058] In one aspect, this application relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0059] .

[0060] In one respect, this application relates to compound A,

[0061] Or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0062] In one respect, this application relates to compound A,

[0063] The method of using it in the treatment or prevention of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0064] In one respect, this application relates to compound A,

[0065] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0066] In one respect, this application relates to compound A,

[0067] Use for preparing a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0068] In one aspect, this application relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0069] Or, or a pharmaceutically acceptable salt thereof.

[0070] In one aspect, this application relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0071] .

[0072] In one respect, this application relates to compound A,

[0073] Or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering to the subject an effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0074] In one respect, this application relates to compound A,

[0075] The compound A is used in a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0076] In one respect, this application relates to compound A,

[0077] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0078] In one respect, this application relates to compound A,

[0079] Use for preparing a medicament for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0080] In one aspect, this application relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0081] Or, or a pharmaceutically acceptable salt thereof.

[0082] In one respect, this application relates to compound A,

[0083] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0084] In one respect, this application relates to compound A,

[0085] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0086] In one aspect, this application relates to a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0087] Or, or a pharmaceutically acceptable salt thereof.

[0088] In one respect, this application relates to compound A,

[0089] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0090] In one respect, this application relates to compound A,

[0091] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0092] In some implementations, SBMA symptoms include fatigue, muscle cramps, weakness in the limbs, difficulty chewing, difficulty swallowing, difficulty speaking, diminished deep tendon reflexes, lack of pathological reflexes, diminished leg vibration sensation, erectile dysfunction, decreased fertility, gynecomastia, testicular atrophy, glucose resistance, hyperlipidemia, fatty liver disease, or a combination thereof.

[0093] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0094] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject in tablet form.

[0095] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject as a solution.

[0096] In some implementations, about 5 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0097] In some implementations, about 50 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0098] In some implementations, about 5 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0099] In some implementations, about 10 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0100] In some implementations, about 15 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0101] In some implementations, about 20 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0102] In some implementations, about 25 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0103] In some implementations, about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0104] In some implementations, approximately 25 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0105] In some implementations, approximately 50 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0106] In some implementations, 75 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0107] In some implementations, approximately 100 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0108] In some implementations, approximately 125 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0109] In some implementations, approximately 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0110] In some implementations, approximately 175 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0111] In some implementations, approximately 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0112] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 25 mg to about 75 mg, about 30 mg to about 80 mg, about 35 mg to about 85 mg, about 40 mg to about 90 mg, about 45 mg to about 95 mg, about 50 mg to about 100 mg, about 55 mg to about 105 mg, about 60 mg to about 110 mg, about 65 mg to about 115 mg, about 70 mg to about 120 mg, or about 75 mg to about 125 mg.

[0113] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 30 mg to about 75 mg, about 35 mg to about 80 mg, about 40 mg to about 85 mg, about 45 mg to about 90 mg, about 50 mg to about 95 mg, about 55 mg to about 100 mg, about 60 mg to about 105 mg, about 65 mg to about 110 mg, about 70 mg to about 115 mg, or about 75 mg to about 120 mg.

[0114] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 35 mg to about 75 mg, about 40 mg to about 80 mg, about 45 mg to about 85 mg, about 50 mg to about 90 mg, about 55 mg to about 95 mg, about 60 mg to about 100 mg, about 65 mg to about 105 mg, about 70 mg to about 110 mg, or about 75 mg to about 110 mg.

[0115] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 40 mg to about 75 mg, about 45 mg to about 80 mg, about 50 mg to about 85 mg, about 55 mg to about 90 mg, about 60 mg to about 95 mg, about 65 mg to about 100 mg, about 70 mg to about 105 mg, or about 75 mg to about 110 mg.

[0116] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 45 mg to about 75 mg, about 50 mg to about 80 mg, about 55 mg to about 85 mg, about 60 mg to about 90 mg, about 65 mg to about 95 mg, about 70 mg to about 100 mg, or about 75 mg to about 105 mg.

[0117] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0118] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0119] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 55 mg to about 75 mg, about 60 mg to about 80 mg, about 65 mg to about 85 mg, about 70 mg to about 90 mg, or about 75 mg to about 95 mg.

[0120] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 60 mg to about 75 mg, about 65 mg to about 80 mg, about 70 mg to about 85 mg, or about 75 mg to about 90 mg.

[0121] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 65 mg to about 75 mg, about 70 mg to about 80 mg, or about 75 mg to about 85 mg.

[0122] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 200 mg to about 500 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 350 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.

[0123] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 250 mg to about 500 mg, about 250 mg to about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, or about 250 mg to about 300 mg.

[0124] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, or 300 mg to about 350 mg.

[0125] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 350 mg to about 500 mg, about 350 mg to about 450 mg, about 350 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg.

[0126] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered to the subject once a day, once every two days, once every three days, or once every four days.

[0127] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0128] In some implementations, the subject is in a state of eating when the medication is administered.

[0129] In some implementations, the subjects are fasting when administered the medication. Attached Figure Description

[0130] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with this specification, serve to explain the principles of the disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate exemplary embodiments of the disclosure, wherein:

[0131] Figure 1 It displays AR degradation (DC) mediated by various compounds in VCaP cells as measured by ELISA (circles) or high-content imaging (squares). 50 Compared to D max A scatter plot of compounds. Each point represents a compound. Compound A is indicated for reference.

[0132] Figure 2A This is a scatter plot showing the potency of various compounds evaluated in myotubes derived from control myoblast cell lines engineered to express polyQ-AR labeled with HiBiT epitopes. Myotubes were treated with the compounds for 24 hours, and PolyQ-AR levels were measured using the Nano-Glo HiBiT cleavage assay kit. Each point represents one compound. Compound A is indicated for reference.

[0133] Figure 2B This is a scatter plot showing the potency of various compounds evaluated in HEK293 cells expressing polyQ-AR. Cells were treated with the compounds for 24 hours, and AR proteins were detected by high-content imaging. Each point represents one compound. Compound A is indicated for reference.

[0134] Figure 2C Is with Figure 2A The same scatter plot is shown, except that all compounds tested in vivo are indicated for reference.

[0135] Figure 2D Is with Figure 2B The same scatter plot is shown, except that all compounds tested in vivo are indicated for reference.

[0136] Figure 3 This is a scatter plot showing the mean AR degradation in LABC muscle from male C57Bl / 6 mice (n=5) administered 30 mg / kg of various compounds via PO. LABC muscle was harvested 24 hours after administration. AR protein in LABC lysates was measured by ELISA and reported as a percentage of LABC in mice administered only with the carrier. Each point represents one compound. Compound A is indicated for reference.

[0137] Figure 4A This is a scatter plot showing AR agonist activity measured in MDA-MB-453 cells engineered with various AR luciferase reporter genes in the presence of pomalidomide to block binding to CRBN and subsequent degradation. Maximum agonist activity is reported as a percentage of agonist activity of R1881 and against EC. 50 Plot the graph. Each point represents a compound. Compounds A and B are indicated for reference.

[0138] Figure 4B The D-values ​​of polyQ-AR in myotube cell nuclei were measured 24 hours after treatment with compound A (left column) and compound B (right column). max .

[0139] Figure 4CThis shows the D-values ​​of polyQ-AR in the nuclei of myotube cells after 24 hours of treatment with various compounds. max DCs targeting AR in myotube cell nuclei 50 A scatter plot. Each point represents a compound. Compounds A and B are indicated for reference.

[0140] Figure 5A This is a dose-response curve plotting the mean polyQ-AR concentration in DMSO-treated cells against the concentration of compound A in hiPSC lines derived from SBMA patients differentiating into myotubes. PolyQ-AR protein was detected by capillary immunoassay, normalized to total protein and mean polyQ-AR concentration in DMSO-treated cells, and plotted against compound A concentration. Curve fitting and DC... 50 and D max The calculation limits the top to 100% in GraphPad Prism.

[0141] Figure 5B This is a dose-response curve plotting the polyQ-AR concentration in DMSO-treated cells against the concentration of the inactive E3 compound (compound F) in hiPSC lines derived from SBMA patients differentiating into myotubes. PolyQ-AR protein was detected by capillary immunoassay, normalized to the total protein and mean PolyQ-AR concentration in DMSO-treated cells, and plotted against concentration. Curve fitting and DC... 50 and D max The calculation limits the top to 100% in GraphPad Prism.

[0142] Figure 6A This is a schematic diagram of the hAR100Q study, which aimed to evaluate muscle function and polyQ-AR degradation in an SBMA mouse model.

[0143] Figure 6B This study shows the change in body weight over time in male hAR100Q mice that began receiving diets formulated with mediator or compound A at 5 weeks of age. Body weight was measured weekly. Two-way ANOVA or a mixed-effects model, followed by Sidac multiple comparison correction, was used to compare the body weights of WT littermates and hAR100Q mice separately. A mixed-effects model was used to explain missing data due to hAR100Q mice that died before 13 weeks of age (****p<.0001).

[0144] Figure 6CThis study shows the change in body weight over time in male WT mice that began receiving a diet formulated with mediator or compound A at 5 weeks of age. Body weight was measured weekly. Two-way ANOVA or a mixed-effects model, followed by Sidac multiple comparison correction, was used to compare the body weights of WT littermates and hAR100Q mice separately. A mixed-effects model was used to explain missing data due to hAR100Q mice that died before 13 weeks of age (****p<.0001).

[0145] Figure 7A This study shows the full paw grip strength of male hAR100Q mice, measured weekly starting at 7 weeks of age and fed diets formulated with mediator or compound A at 5 weeks of age. Grip strength was compared between WT littermates and hAR100Q mice separately using either ANOVA or a mixed-effects model (treatment x time), followed by Sidac multiple comparison correction. A mixed-effects model was used to explain missing data due to hAR100Q mice that died before 13 weeks of age. Statistical differences between groups were assessed using a two-way ANOVA (treatment x genotype) (****p<.0001).

[0146] Figure 7B This study shows the whole-paw grip strength of male littermate control mice that began receiving a diet formulated with mediator or compound A at 5 weeks of age, measured weekly starting at 7 weeks of age. Grip strength was compared between WT littermates and hAR100Q mice separately using ANOVA or a mixed-effects model (treatment x time), followed by Sidac multiple comparison correction. A mixed-effects model was used to explain missing data due to hAR100Q mice that died before 13 weeks of age. Statistical differences between groups were assessed using two-way ANOVA (treatment x genotype) (****p<.0001).

[0147] Figure 7C Muscle endurance was measured by forced treadmill performance in WT and hAR100Q mice administered compound A (15 mg / kg) or the mediator at 11 weeks of age. Statistical differences between groups were assessed using two-way ANOVA (treatment x genotype) (****p<.0001).

[0148] Figure 8A This is a series of capillary blot experiments demonstrating that compound A induces the degradation of AR and polyQ-AR (hAR100Q) but not the degradation of high molecular weight polyQ-AR (HMW hAR100Q) in the LABC muscle of an SBMA mouse model. Compound A induces the degradation of WT AR in the LABC of an SBMA mouse model, resulting in a 77% reduction compared to the mediator. Figure 8BCompound A induced the degradation of polyQ-AR (hAR100Q) in the LABC of the SBMA mouse model, resulting in a 70% reduction compared to the mediator. Figure 8C Compound A did not induce the degradation of high molecular weight polyQ-AR (HMW hAR100Q) in the LABC model of the SBMA mouse. Figure 8D ).

[0149] Figure 8E This is a series of capillary blot experiments demonstrating that compound A induces the degradation of polyQ-AR (hAR100Q) in the quadriceps femoris muscle of transgenic AR100Q mice (*indicates that the sample was not properly loaded and was therefore excluded from the analysis). Compound A induces the degradation of WT AR in the quadriceps femoris muscle of SBMA mouse models, resulting in a 65% reduction compared to the mediator. Figure 8F Compound A induced the degradation of polyQ-AR (hAR100Q) in the quadriceps femoris muscle of AR100Q mice, resulting in a 43% reduction ( Figure 8G The reduction of high molecular weight polyQ-AR (HMW hAR100Q) tends to decrease ( Figure 8H ).

[0150] Figure 9 This is a Kaplan-Meier plot showing the survival rate of male hAR100Q mice that were given a diet formulated with mediator or compound A at 5 weeks of age. Survival was defined as the length of time from birth to euthanasia. Mice were euthanized when they were considered to be in a dying state. We assessed the differences in survival by Kaplan-Meier estimation and compared them using a log-rank test.

[0151] Figure 10 This is a schematic diagram illustrating a screening layer specifically designed to identify compounds with desired activity against PolyQ-AR in cell types (myotubules) and tissues (muscle) severely affected by SBMA.

[0152] Figure 11 This is a representative dose-response curve plotting the mean AR concentration in DMSO-treated cells against the concentration of compound A in hiPSC lines derived from SBMA patients differentiating into myotubes. The experiment was conducted in the presence of physiologically relevant concentrations of the androgen dihydrotestosterone (DHT) and demonstrated that compound A induces degradation under these conditions.

[0153] Figure 12A The results showed that, compared with the control, compound A (12 nM) induced the degradation of polyQ-AR, while compound F (12 nM) did not induce degradation.

[0154] Figure 12BThis demonstrates the specificity of compound A for the degradation of polyQ-AR in SBMA hiPSC-myotubules. A single novel substrate exists: PDE6D with compound A. PDE6D is not a novel substrate for the E3 inactive form of compound A, i.e., compound F (… Figure 12C ).

[0155] Figure 13A and Figure 13B Dose-response curves for compound A in plasma and LABC muscle are provided. Figure 13C The results showed that after administration of compound A (30 mg / kg, once daily (QD) for 3 days), the AR level in LABC muscle returned to normal within approximately 3 days.

[0156] sequence list

[0157] All references to amino acid mutations in the androgen receptor are numbered relative to SEQ ID NO: 1 provided below:

[0158] 1 MEVQLGLGRV YPRPPSKTYR GAFQNLFQSV REVIQNPGPR HPEAASAAPP GASLLLLQQQ

[0159] 61 QQQQQQQQQQ QQQQQQQQQQ ETSPRQQQQQ QGEDGSPQAH RRGPTGYLVL DEEQQPSQPQ

[0160] 121 SALECHPERG CVPEPGAAVA ASKGLPQQLP APPDEDDSAA PSTLSLLGPT FPGLSSCSAD

[0161] 181 LKDILSEAST MQLLQQQQQE AVSEGSSSGR AREASGAPTS SKDNYLGGTS TISDNAKELC

[0162] 241 KAVSVSMGLG VEALEHLSPG EQLRGDCMYA PLLGVPPAVR PTPCAPLAEC KGSLLDDSAG

[0163] 301 KSTEDTAEYS PFKGGYTKGL EGESLGCSGS AAAGSSGTLE LPSTLSLYKS GALDEAAAYQ

[0164] 361 SRDYYNFPLA LAGPPPPPPP PHPHARIKLE NPLDYGSAWA AAAAQCRYGD LASLHGAGAA

[0165] 421 GPGSGSPSAA ASSSWHTLFT AEEGQLYGPC GGGGGGGGGG GGGGGGGGGG GGGEAGAVAP

[0166] 481 YGYTRPPQGL AGQESDFTAP DVWYPGGMVS RVPYPSPTCV KSEMGPWMDS YSGPYGDMRL

[0167] 541 ETARDHVLPI DYYFPPQKTC LICGDEASGC HYGALTCGSC KVFFKRAAEG KQKYLCASRN

[0168] 601 DCTIDKFRRK NCPSCRLRKC YEAGMTLGAR KLKKLGNLKL QEEGEASSTT SPTEETTQKL

[0169] 661 TVSHIEGYEC QPIFLNVLEA IEPGVVCAGH DNNQPDSFAA LLSSLNELGE RQLVHVVKWA

[0170] 721 KALPGFRNLH VDDQMAVIQY SWMGLMVFAM GWRSFTNVNS RMLYFAPDLV FNEYRMHKSR

[0171] 781 MYSQCVRMRH LSQEFGWLQI TPQEFLCMKA LLLFSIIPVD GLKNQKFFDE LRMNYIKELD

[0172] 841 RIIACKRKNP TSCSRRFYQL TKLLDSVQPI ARELHQFTFD LLIKSHMVSV DFPEMMAEII

[0173] 901 SVQVPKILSG KVKPIYFHTQ

[0174] abbreviation

[0175] ANOVA Analysis of variance AR androgen receptor ASO antisense oligonucleotides BAC Bacterial artificial chromosomes BSA Bovine serum albumin CRBN Human cerebellum protein DC Detergent compatible DMEM Durbeck Modified Eagle Medium DMSO Dimethyl sulfoxide ELISA Enzyme-linked immunosorbent assay ELN Electronic Lab Notebook FBS fetal bovine serum HEK PQ HEK 293 polyQ androgen receptor hiSPC Human induced pluripotent stem cells HRP Horseradish peroxidase IACUC Institutional Animal Care and Use Committee KO Knockout LABC Levator ani / bulbospongiosus muscle LBD ligand binding domain MyHC Myosin heavy chain NIR Near-infrared PCR Polymerase chain reaction PDL Poly-D-Lysine PEG polyethylene glycol PFA Paraformaldehyde PO Oral administration RIPA Radioimmunoprecipitation assay RPMI Roswell Park Memorial Institute SBMA Spinal bulbar muscular atrophy SDS Sodium dodecyl sulfate TBS Tris buffer saline WT wild type Detailed Implementation

[0176] definition

[0177] In one aspect, this application relates to the use of compounds for inducing the degradation of the polyQ-AR protein. Effective, selective, orally bioavailable compounds for inducing AR degradation have been developed for the treatment of metastatic castration-resistant prostate cancer (see, for example, U.S. Patent No. 10,584,101).

[0178] These compounds (also known as PROTACs (proteolytic-targeting chimeras)) are chimeric small molecules that bind to an E3 ligase and a target to promote protein degradation by presenting the E3 ligase complex to the target protein, leading to ubiquitination of the target protein, which is then degraded via the cell's natural and selective ubiquitin-proteasome system. Not wanting to be bound by theory, the compounds may effectively induce the degradation of polyQ-AR proteins because polyQ amplification in exon 1 of AR is unlikely to disrupt the LBD binding site near the C-terminus. As described in this paper, the pharmacology of degrading polyQ-amplified AR is unexpectedly different from that of wild-type AR (<38Q), resulting in enhanced activity of polyQ AR in muscle cells and enhanced pharmacodynamic effects in muscle.

[0179] In one aspect, this application relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject, comprising administering an effective amount of compound A to the subject in need.

[0180] Or, or a pharmaceutically acceptable salt thereof.

[0181] In one aspect, this application relates to a method of treating or preventing SBMA in a subject in need, comprising administering an effective amount of compound A to the subject.

[0182] In one aspect, this application relates to a method of treating or preventing SBMA symptoms in a subject in need, comprising administering to the subject an effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0183] In one aspect, this application relates to a method of treating or preventing SBMA symptoms in a subject in need, comprising administering an effective amount of compound A to the subject.

[0184] In some implementations, SBMA symptoms include fatigue, muscle cramps, weakness in the limbs, difficulty chewing, difficulty swallowing, difficulty speaking, diminished deep tendon reflexes, lack of pathological reflexes, diminished leg vibration sensation, erectile dysfunction, decreased fertility, gynecomastia, testicular atrophy, glucose resistance, hyperlipidemia, fatty liver disease, or a combination thereof.

[0185] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0186] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once, twice, three times, or four times a day.

[0187] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once a day, once every two days, once every three days, or once every four days.

[0188] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0189] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every two days.

[0190] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every three days.

[0191] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every four days.

[0192] In some implementations, the subject is in a state of eating when the medication is administered.

[0193] In some implementations, the subjects are fasting when administered the medication.

[0194] All references to amino acid mutations in the androgen receptor are numbered relative to SEQ ID NO: 1 provided herein.

[0195] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins for targeted degradation. For example, human cerebellar protein (CRBN) is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, causes ubiquitin to attach to a lysine residue on a target protein and subsequently targets a specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugate, are responsible for transferring ubiquitin to the target protein. Generally, ubiquitin ligases involve polyubiquitination, where a second ubiquitin attaches to a first ubiquitin; a third ubiquitin attaches to a second ubiquitin, and so on. Polyubiquitinated proteins are labeled for degradation via the proteasome. However, there are also ubiquitination events limited to monoubiquitination, where the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins do not target the proteasome for degradation but can instead alter their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, E3 can target different lysine residues on ubiquitin to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin that is recognized by the proteasome.

[0196] As used herein, "pharmaceutically acceptable salt" refers to the salt form of compound A and the hydrate of that salt form with one or more present water molecules. Such salt and hydrate forms retain the biological activity of the compounds disclosed herein and exhibit minimal (if any) toxicological effects in non-biological or other undesirable respects. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium, calcium edetate, camphorsulfonates, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonate, propionate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-p-aminobenzoarsylate, gluconate, glutamate, glycolyl-p-aminobenzoarsylate, hexafluorophosphate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, and iodides. Isothiosulfates, lactates, lacturonates, laurates, magnesium, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, bis(hydroxynaphthoate) (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, theochloroate, toluenesulfonates, triethyliodide, and valerates.

[0197] As used herein, "solvent" refers to the solvation form of compound A, which contains stoichiometric or non-stoichiometric amounts of solvent. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the formed solvate is a hydrate; when the solvent is an alcohol, the formed solvate is an alcoholate. Hydrates are formed by a combination of one or more water molecules with one of the substances in which water retains its molecular state as H₂O; such combinations can form one or more hydrates. In hydrates, water molecules are linked by intermolecular forces, particularly hydrogen bridges, via secondary valences. Solid hydrates contain water in a stoichiometric ratio, known as crystalline water, where the water molecules need not be identical in their bonding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, or trihydrates. Also suitable are hydrates of salts of the compounds disclosed herein.

[0198] As used herein, “treatment” describes the management and care of a subject for the purpose of combating a disease, symptom or condition, or reversing, alleviating or inhibiting the progression of a disease, symptom or condition, and also includes reducing or alleviating symptoms or complications, or eliminating a disease, symptom or condition.

[0199] Unless otherwise stated, the term “treatment” as used herein refers to the act of “treatment” as defined above. For example, the terms “treat,” “treating,” and “treatment” can refer to methods of alleviating or eliminating a particular condition and / or one or more of its accompanying symptoms.

[0200] As used in this article, "subject" refers to a person or an animal (in the case of an animal, the subject can be a mammal). In one respect, the subject is a person. In another respect, the subject is male.

[0201] As used in this article, “prevention” describes stopping the onset of symptoms or complications of a disease, condition, or illness.

[0202] "Administration" refers to the introduction of a drug (such as compound A) into a subject's body. The related terms "administering" and "administration of" (and their grammatical equivalents) both refer to direct administration, which can be given to a subject by a medical professional or administered by the subject themselves; and / or indirect administration, which can be the act of prescribing a drug. For example, a physician instructing a patient to administer a drug themselves and / or prescribing a drug to a patient administers the drug to the patient.

[0203] The terms "co-administration" and "co-administering" or "combination therapy" refer to simultaneous administration (the simultaneous administration of two or more therapeutic agents) and time-varying administration (the administration of one or more therapeutic agents at a different time than the administration of another one or more therapeutic agents), provided that the therapeutic agents are present in the patient to a certain extent, preferably in an effective amount. In some preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional bioactive agent.

[0204] As used herein, “effective amount” means the amount of the free base of compound A, or an equivalent amount of a pharmaceutically acceptable salt of compound A, sufficient to treat, improve, or prevent symptoms of SBMA or SMBA, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. An effective amount for a particular subject may depend on the subject’s weight, body size, and health status; the nature and severity of the symptoms; and whether additional therapeutic agents are to be administered to the subject. An effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0205] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt of compound A means that, when administered to a subject with SBMA or SBMA symptoms, it causes 50% or more AR degradation in the affected muscle of the subject compared to the affected muscle of a subject who has not been administered compound A.

[0206] As used in this article, “C” max "" refers to the maximum (peak) plasma concentration of a specific compound observed in a subject after administering a dose of that compound.

[0207] The term “about” as part of a quantitative expression such as “about X” includes any value higher or lower than 10% of X, and also includes any value falling between X-10% and X+10%. Thus, for example, about 40 g contains a weight of 36 to 44 g. When used herein to refer to amino acid residues in AR, the term “about” refers to any amino acid residue within a specified set of 5 amino acid residues. For example, when referring to a continuous sequence of amino acid residues extending from about amino acid residue 560 to about amino acid residue 624 in AR, this refers to a continuous sequence of amino acid residues extending from amino acid residues 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, or 565 in AR of SEQ ID NO: 1 to amino acid residues 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 three amino acid residues. In some embodiments, the term "about" means any amino acid residue within the specified one amino acid residue.

[0208] Compound A disclosed herein refers to N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide, which has the following structure:

[0209] (Compound A).

[0210] Compound A can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules, as well as for the transformation and manipulation of functional groups, including the use of protecting groups. These methods and procedures are available from relevant scientific literature or from standard reference textbooks in the art, in light of this disclosure. While not limited to any one or more sources, recognized reference textbooks for organic synthesis include: Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3rd edition; John Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2023 / 0331681 and International Publication No. 2018 / 144649 are incorporated herein by reference in their entirety.

[0211] As used in this article, "compound B" refers to a compound having the following structure:

[0212] .

[0213] As used in this article, "compound C" refers to a compound having the following structure:

[0214] .

[0215] As used in this article, "compound D" refers to a compound having the following structure:

[0216] .

[0217] As used herein, “compound E” refers to a compound having the following structure:

[0218] .

[0219] As used in this article, "compound F" refers to a compound having the following structure:

[0220] Compound F is a modified form of compound A, which does not bind to human cerebellar protein (CRBN) E3 ubiquitin ligase.

[0221] As used herein, “R1881”, namely (8S,13S,14S,17S)-17-hydroxy-13,17-dimethyl-1,2,6,7,8,14,15,16-octahydrocyclopenta[a]phenanthrene-3-one, is a synthetic AR agonist, also known as metribolone or methyltrienolone. The structure of R1881 is:

[0222] .

[0223] When used to describe or claim a particular dosage form, composition, use, method, or process, "comprising" means that the dosage form, composition, use, method, or process includes all the elements described or claimed herein, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the physical, pharmacological, pharmacokinetic, or therapeutic properties of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" mean excluding other components beyond trace elements and substantial method or process steps.

[0224] The term "fasting status" or "fasting condition" used to describe a subject means that the subject has not eaten for at least 4 hours prior to the time point of interest, such as the time of administration of the compound of this disclosure (preferably compound A or a pharmaceutically acceptable salt thereof). In one embodiment, the subject in a fasting status has not eaten for at least any one of 6 hours, 8 hours, 10 hours, or 12 hours prior to administration of the compound of this disclosure (preferably compound A or a pharmaceutically acceptable salt thereof).

[0225] In this document, the term "eating status" or "feeding condition" used to describe a subject means that the subject ate less than 4 hours prior to the time point of interest, such as the time of administration of the compound of this disclosure (preferably compound A or a pharmaceutically acceptable salt thereof). In one embodiment, a subject in a feeding condition ate within at least any one of at least 3 hours, 2 hours, 1 hour, or 0.5 hours prior to administration of the compound of this disclosure (preferably compound A or a pharmaceutically acceptable salt thereof).

[0226] In this disclosure, the article “a / an” is used to refer to one or more (i.e., at least one) grammatical objects of the article. By way of example, “a element” means one element or more elements.

[0227] Unless otherwise stated, the term “and / or” is used in this disclosure to mean “and” or “or”.

[0228] The terms “patient” and “subject” are used interchangeably in this document and refer to mammals such as humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates such as monkeys, chimpanzees, baboons, or rhesus monkeys.

[0229] As used herein, the term "bioactive agent" refers to compounds or agents other than compound A that treat or prevent SBMA and / or SBMA symptoms.

[0230] In some implementations, the subject is a person. In some implementations, the subject is male.

[0231] In some implementations, the subjects are people diagnosed with spinal bulbar muscular atrophy (SBMA).

[0232] Methods for ubiquitination / degradation of target proteins in cells

[0233] This disclosure provides a method for ubiquitinizing / degrading a target protein in cells. The method includes administering compound A or a pharmaceutically acceptable salt thereof, comprising an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety (as otherwise described herein) linked by a linker portion, wherein the E3 ubiquitin ligase-binding moiety is coupled to the protein-targeting moiety, and wherein the E3 ubiquitin ligase-binding moiety recognizes ubiquitin pathway proteins (e.g., ubiquitin ligases, preferably E3 ubiquitin ligases) and the protein-targeting moiety recognizes the target protein, such that when the target protein is in the vicinity of the ubiquitin ligase, the target protein is degraded, thereby resulting in degradation / inhibition of the target protein's action and control of protein levels. The control of protein levels provided by this disclosure provides treatment for disease states or symptoms that are regulated by target proteins by reducing the levels of said proteins in the patient's cells.

[0234] As understood by those skilled in the art, the 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 MolBiol. (1997) 62:233-42). The DNA-binding domain is hinged to the ligand-binding domain. The AR ligand-binding domain is the functional domain of the human AR that folds to form a hydrophobic pocket for binding to AR homologous hormone ligands (e.g., androgens).

[0235] Furthermore, it should be understood in the art that the 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 in SEQ ID NO: 1 and identified in the UniProt database as P10275 (ANDR_HUMAN). The gene encoding AR (“AR gene”) is approximately 90 kb in length and has chromosomal coordinates 67544021-67730619 according to the human reference genome GRCh38.p13. The AR gene contains eight exons, of which 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).

[0236] In one aspect, this application provides compound A or a pharmaceutically acceptable salt thereof that degrades androgen receptor (AR) proteins. In some embodiments, the AR degraded by compound A or a pharmaceutically acceptable salt thereof is wild-type AR. In some embodiments, the AR degraded by compound A or a pharmaceutically acceptable salt thereof is a mutant form of AR. In some embodiments, the AR mutation comprises >36 consecutive base pairs of cytosine, adenine, guanine (CAG) repeated in the gene encoding AR, resulting in polyglutamine (polyQ) amplification.

[0237] In some embodiments, this disclosure relates to a method of treating a patient with a disease state or condition requiring protein regulation, wherein the degradation of the protein will produce a therapeutic effect in the patient, the method comprising, optionally in combination with an additional bioactive agent, administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the patient in need. The disease state or condition may be a disease caused by microbial agents or other exogenous agents (e.g., viruses, bacteria, fungi, protozoa, or other microorganisms), or it may be a disease state caused by the overexpression of a protein, leading to the disease state and / or condition.

[0238] Treatment

[0239] In one aspect, this application relates to a method of treating spinal bulbar muscular atrophy (SBMA), comprising administering to a subject in need an effective amount of compound A or a pharmaceutically acceptable salt or solvate thereof.

[0240] In one aspect, this application relates to a method for preventing SBMA, comprising administering to a subject in need an effective amount of compound A or a pharmaceutically acceptable salt or solvate thereof.

[0241] In one aspect, this application relates to a method of treating and / or preventing SBMA, comprising administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to a subject in need.

[0242] In one aspect, this application relates to a method of treating and / or preventing SBMA, comprising administering an effective amount of compound A or a pharmaceutically acceptable salt or solvate thereof to a subject in need in combination with one or more other bioactive agents.

[0243] In one aspect, this application relates to a method of treating and / or preventing SBMA, comprising administering an effective amount of compound A to a subject in need.

[0244] This disclosure relates to a method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0245] Or, or a pharmaceutically acceptable salt thereof.

[0246] This disclosure relates to a method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0247] .

[0248] This disclosure relates to compound A,

[0249] Or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0250] This disclosure relates to compound A,

[0251] The method of using it in treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0252] This disclosure relates to compound A,

[0253] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0254] This disclosure relates to compound A,

[0255] Use for preparing a medicament for treating spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0256] This disclosure relates to a method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0257] Or, or a pharmaceutically acceptable salt thereof.

[0258] This disclosure relates to a method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0259] .

[0260] This disclosure relates to compound A,

[0261] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0262] This disclosure relates to compound A,

[0263] The compound A is used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering about 1 mg to about 500 mg of compound A to the subject.

[0264] This disclosure relates to compound A,

[0265] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0266] This disclosure relates to compound A,

[0267] Use for preparing a medicament for treating spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A, and the medicament is administered to a subject in need.

[0268] This disclosure relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0269] Or, or a pharmaceutically acceptable salt thereof.

[0270] This disclosure relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0271] .

[0272] This disclosure relates to compound A,

[0273] Or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0274] This disclosure relates to compound A,

[0275] The method of using it in treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method includes administering an effective amount of compound A to the subject.

[0276] This disclosure relates to compound A,

[0277] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0278] This disclosure relates to compound A,

[0279] Use for preparing a medicament for treating symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A, and the medicament is administered to a subject in need.

[0280] This disclosure relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0281] Or, or a pharmaceutically acceptable salt thereof.

[0282] This disclosure relates to a method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0283] .

[0284] This disclosure relates to compound A,

[0285] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0286] This disclosure relates to compound A,

[0287] The compound A is used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering about 1 mg to about 500 mg of compound A to the subject.

[0288] This disclosure relates to compound A,

[0289] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0290] This disclosure relates to compound A,

[0291] Use for preparing a medicament for treating symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A, and the medicament is administered to a subject in need.

[0292] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0293] Or, or a pharmaceutically acceptable salt thereof.

[0294] This disclosure relates to compound A,

[0295] Or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0296] This disclosure relates to compound A,

[0297] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0298] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0299] Or, or a pharmaceutically acceptable salt thereof.

[0300] This disclosure relates to compound A,

[0301] Or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering to the subject an effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0302] This disclosure relates to compound A,

[0303] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0304] In some implementations, SBMA symptoms include fatigue, muscle cramps, weakness in the limbs, difficulty chewing, difficulty swallowing, difficulty speaking, diminished deep tendon reflexes, lack of pathological reflexes, diminished vibration sensation in the legs, erectile dysfunction, decreased fertility, gynecomastia, testicular atrophy, glucose resistance, hyperlipidemia, fatty liver disease, or a combination thereof. In some implementations, two or more symptoms are treated or prevented. In some implementations, three or more symptoms are treated or prevented.

[0305] In some implementations, the symptom of SBMA is fatigue.

[0306] In some implementations, the symptom of SBMA is muscle spasms.

[0307] In some implementations, the symptom of SBMA is weakness in the limbs.

[0308] In some implementations, the symptom of SBMA is difficulty chewing.

[0309] In some implementations, the symptom of SBMA is difficulty swallowing.

[0310] In some implementations, the symptom of SBMA is difficulty speaking.

[0311] In some implementations, the symptom of SBMA is diminished deep tendon reflexes.

[0312] In some implementations, the symptom of SBMA is a lack of pathological reflexes.

[0313] In some implementations, the symptoms of SBMA include a diminished or absent sensation of vibration in the legs.

[0314] In some implementations, the symptom of SBMA is erectile dysfunction.

[0315] In some implementations, the symptom of SBMA is reduced fertility.

[0316] In some implementations, the symptom of SBMA is gynecomastia.

[0317] In some implementations, the symptom of SBMA is testicular atrophy.

[0318] In some implementations, the symptom of SBMA is glucose resistance.

[0319] In some implementation schemes, the symptom of SBMA is the absence of hyperlipidemia.

[0320] In some implementations, SBMA symptoms are fatty liver disease.

[0321] Compound A or a pharmaceutically acceptable salt thereof may be administered orally, parenterally, topically, intramuscularly, intravenously, subcutaneously, transdermally, orally, sublingually, or via suppositories, in single or multiple doses.

[0322] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, compound A is administered orally to a subject.

[0323] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject in tablet form.

[0324] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject as a solution.

[0325] An effective amount of compound A or a pharmaceutically acceptable salt thereof may be administered once or multiple times a day for up to 30 days or more, followed by one or more days without administration of the compound. This type of treatment schedule (i.e., several consecutive days of administration of compound A, followed by several consecutive days without administration of compound A) is called a treatment cycle. Treatment cycles may be repeated as needed to achieve the desired effect.

[0326] In some implementations, the effective amount of compound A or a pharmaceutically acceptable salt thereof is between 1 mg and about 1,000 mg, administered to a subject once, twice, three times, four times or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty-five, or thirty consecutive days, or once, twice, three times, four times or more daily for two, three, four, five, six months or longer.

[0327] In some implementations, the effective amount of compound A or a pharmaceutically acceptable salt thereof is between 1 mg and about 1,000 mg, administered to a subject in a single dose or in divided doses every two days, every three days, every four days, every five days, every six days, every seven days or less for a duration of 2 months, 3 months, 4 months, 5 months, 6 months or longer.

[0328] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0329] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered once every four days.

[0330] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered once every three days.

[0331] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered every two days.

[0332] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered once daily.

[0333] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered twice daily.

[0334] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered three times daily.

[0335] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally once every four days.

[0336] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally once every three days.

[0337] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally once every two days.

[0338] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally once daily.

[0339] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally twice daily.

[0340] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally three times daily.

[0341] In some embodiments, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once. In some embodiments, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject in two portions (i.e., divided doses). In some embodiments, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject in three divided doses. In some embodiments, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject in four divided doses. In some embodiments, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject in five or more divided doses. In some embodiments, a portion of compound A or a pharmaceutically acceptable salt thereof is administered to the subject at regular intervals throughout the day, such as every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0342] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0343] Or, or a pharmaceutically acceptable salt thereof.

[0344] This disclosure relates to compound A,

[0345] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0346] This disclosure relates to compound A,

[0347] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0348] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0349] Or, or a pharmaceutically acceptable salt thereof.

[0350] This disclosure relates to compound A,

[0351] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0352] This disclosure relates to compound A,

[0353] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0354] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 30 mg to about 150 mg of compound A:

[0355] Or, or a pharmaceutically acceptable salt thereof.

[0356] This disclosure relates to compound A,

[0357] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof.

[0358] This disclosure relates to compound A,

[0359] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0360] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 30 mg to about 150 mg of compound A:

[0361] Or, or a pharmaceutically acceptable salt thereof.

[0362] This disclosure relates to compound A,

[0363] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof.

[0364] This disclosure relates to compound A,

[0365] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0366] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 50 mg to about 100 mg of compound A:

[0367] Or, or a pharmaceutically acceptable salt thereof.

[0368] This disclosure relates to compound A,

[0369] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 50 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof.

[0370] This disclosure relates to compound A,

[0371] The use of compound A or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 50 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0372] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 50 mg to about 100 mg of compound A:

[0373] Or, or a pharmaceutically acceptable salt thereof.

[0374] This disclosure relates to compound A,

[0375] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 50 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof.

[0376] This disclosure relates to compound A,

[0377] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 50 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0378] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 70 mg to about 100 mg of compound A:

[0379] Or, or a pharmaceutically acceptable salt thereof.

[0380] This disclosure relates to compound A,

[0381] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 70 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof.

[0382] This disclosure relates to compound A,

[0383] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 70 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0384] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 70 mg to about 100 mg of compound A:

[0385] Or, or a pharmaceutically acceptable salt thereof.

[0386] This disclosure relates to compound A,

[0387] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to said subject about 70 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof.

[0388] This disclosure relates to compound A,

[0389] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 70 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0390] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 100 mg to about 200 mg of compound A:

[0391] Or, or a pharmaceutically acceptable salt thereof.

[0392] This disclosure relates to compound A,

[0393] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering to the subject about 100 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof.

[0394] This disclosure relates to compound A,

[0395] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 100 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0396] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 100 mg to about 200 mg of compound A:

[0397] Or, or a pharmaceutically acceptable salt thereof.

[0398] This disclosure relates to compound A,

[0399] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 100 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof.

[0400] This disclosure relates to compound A,

[0401] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 100 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0402] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 150 mg to about 250 mg of compound A:

[0403] Or, or a pharmaceutically acceptable salt thereof.

[0404] This disclosure relates to compound A,

[0405] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 150 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof.

[0406] This disclosure relates to compound A,

[0407] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 150 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0408] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 150 mg to about 250 mg of compound A:

[0409] Or, or a pharmaceutically acceptable salt thereof.

[0410] This disclosure relates to compound A,

[0411] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 150 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof.

[0412] This disclosure relates to compound A,

[0413] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 150 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0414] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 200 mg to about 300 mg of compound A:

[0415] Or, or a pharmaceutically acceptable salt thereof.

[0416] This disclosure relates to compound A,

[0417] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering about 200 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0418] This disclosure relates to compound A,

[0419] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 200 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0420] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 200 mg to about 300 mg of compound A:

[0421] Or, or a pharmaceutically acceptable salt thereof.

[0422] This disclosure relates to compound A,

[0423] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 200 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof.

[0424] This disclosure relates to compound A,

[0425] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 200 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0426] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 250 mg to about 350 mg of compound A:

[0427] Or, or a pharmaceutically acceptable salt thereof.

[0428] This disclosure relates to compound A,

[0429] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 250 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof.

[0430] This disclosure relates to compound A,

[0431] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 250 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0432] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 250 mg to about 350 mg of compound A:

[0433] Or, or a pharmaceutically acceptable salt thereof.

[0434] This disclosure relates to compound A,

[0435] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 250 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof.

[0436] This disclosure relates to compound A,

[0437] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 250 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0438] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 300 mg to about 400 mg of compound A:

[0439] Or, or a pharmaceutically acceptable salt thereof.

[0440] This disclosure relates to compound A,

[0441] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering to the subject about 300 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof.

[0442] This disclosure relates to compound A,

[0443] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 300 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0444] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 300 mg to about 400 mg of compound A:

[0445] Or, or a pharmaceutically acceptable salt thereof.

[0446] This disclosure relates to compound A,

[0447] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 300 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof.

[0448] This disclosure relates to compound A,

[0449] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 300 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0450] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 350 mg to about 450 mg of compound A:

[0451] Or, or a pharmaceutically acceptable salt thereof.

[0452] This disclosure relates to compound A,

[0453] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein the method comprises administering to the subject about 350 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof.

[0454] This disclosure relates to compound A,

[0455] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 350 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0456] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 350 mg to about 450 mg of compound A:

[0457] Or, or a pharmaceutically acceptable salt thereof.

[0458] This disclosure relates to compound A,

[0459] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 350 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof.

[0460] This disclosure relates to compound A,

[0461] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 350 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0462] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 400 mg to about 500 mg of compound A:

[0463] Or, or a pharmaceutically acceptable salt thereof.

[0464] This disclosure relates to compound A,

[0465] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 400 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0466] This disclosure relates to compound A,

[0467] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 400 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0468] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 400 mg to about 500 mg of compound A:

[0469] Or, or a pharmaceutically acceptable salt thereof.

[0470] This disclosure relates to compound A,

[0471] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 400 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0472] This disclosure relates to compound A,

[0473] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 400 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0474] This disclosure relates to a method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering approximately 75 mg of compound A to the subject:

[0475] Or, or a pharmaceutically acceptable salt thereof.

[0476] This disclosure relates to compound A,

[0477] Or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering about 75 mg of compound A or a pharmaceutically acceptable salt thereof to said subject.

[0478] This disclosure relates to compound A,

[0479] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 75 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0480] This disclosure relates to a method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering approximately 75 mg of compound A to the subject:

[0481] Or, or a pharmaceutically acceptable salt thereof.

[0482] This disclosure relates to compound A,

[0483] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering about 75 mg of compound A or a pharmaceutically acceptable salt thereof to said subject.

[0484] This disclosure relates to compound A,

[0485] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 75 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0486] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered to the subject once, twice, three times, or four times a day.

[0487] In some implementations, compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0488] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every two days.

[0489] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every three days.

[0490] In some implementations, an effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every four days.

[0491] In some implementations, about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0492] In some implementations, about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every two days.

[0493] In some implementations, about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every three days.

[0494] In some implementations, about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once every four days.

[0495] In some implementations, about 1 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0496] In some implementations, about 5 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0497] In some implementations, about 10 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0498] In some implementations, about 15 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0499] In some implementations, about 20 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0500] In some implementations, about 25 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0501] In some implementations, about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0502] In some implementations, about 35 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0503] In some implementations, approximately 10 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0504] In some implementations, approximately 25 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0505] In some implementations, approximately 50 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0506] In some implementations, approximately 75 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0507] In some implementations, approximately 100 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0508] In some implementations, approximately 125 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0509] In some implementations, approximately 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0510] In some implementations, approximately 175 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0511] In some implementations, approximately 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0512] In some implementations, approximately 225 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0513] In some implementations, approximately 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0514] In some implementations, approximately 275 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0515] In some implementations, approximately 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0516] In some implementations, approximately 325 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0517] In some implementations, approximately 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0518] In some implementations, approximately 375 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0519] In some implementations, approximately 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0520] In some implementations, approximately 425 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0521] In some implementations, approximately 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0522] In some implementations, approximately 475 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0523] In some implementations, approximately 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0524] In some implementations, about 200 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0525] In some implementations, about 200 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0526] In some implementations, about 200 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0527] In some implementations, about 200 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0528] In some implementations, about 200 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0529] In some implementations, about 200 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0530] In some implementations, about 250 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0531] In some implementations, about 250 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0532] In some implementations, about 250 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0533] In some implementations, about 250 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0534] In some implementations, about 250 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0535] In some implementations, about 300 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0536] In some implementations, about 300 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0537] In some implementations, about 300 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0538] In some implementations, about 300 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0539] In some implementations, about 350 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0540] In some implementations, about 350 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0541] In some implementations, about 350 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0542] In some implementations, about 400 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0543] In some implementations, about 400 mg to about 450 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0544] In some implementations, about 450 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0545] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 25 mg to about 75 mg, about 30 mg to about 80 mg, about 35 mg to about 85 mg, about 40 mg to about 90 mg, about 45 mg to about 95 mg, about 50 mg to about 100 mg, about 55 mg to about 105 mg, about 60 mg to about 110 mg, about 65 mg to about 115 mg, about 70 mg to about 120 mg, or about 75 mg to about 125 mg.

[0546] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 30 mg to about 75 mg, about 35 mg to about 80 mg, about 40 mg to about 85 mg, about 45 mg to about 90 mg, about 50 mg to about 95 mg, about 55 mg to about 100 mg, about 60 mg to about 105 mg, about 65 mg to about 110 mg, about 70 mg to about 115 mg, or about 75 mg to about 120 mg.

[0547] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 35 mg to about 75 mg, about 40 mg to about 80 mg, about 45 mg to about 85 mg, about 50 mg to about 90 mg, about 55 mg to about 95 mg, about 60 mg to about 100 mg, about 65 mg to about 105 mg, about 70 mg to about 110 mg, or about 75 mg to about 110 mg.

[0548] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 40 mg to about 75 mg, about 45 mg to about 80 mg, about 50 mg to about 85 mg, about 55 mg to about 90 mg, about 60 mg to about 95 mg, about 65 mg to about 100 mg, about 70 mg to about 105 mg, or about 75 mg to about 110 mg.

[0549] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 45 mg to about 75 mg, about 50 mg to about 80 mg, about 55 mg to about 85 mg, about 60 mg to about 90 mg, about 65 mg to about 95 mg, about 70 mg to about 100 mg, or about 75 mg to about 105 mg.

[0550] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0551] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0552] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 55 mg to about 75 mg, about 60 mg to about 80 mg, about 65 mg to about 85 mg, about 70 mg to about 90 mg, or about 75 mg to about 95 mg.

[0553] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 60 mg to about 75 mg, about 65 mg to about 80 mg, about 70 mg to about 85 mg, or about 75 mg to about 90 mg.

[0554] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 65 mg to about 75 mg, about 70 mg to about 80 mg, or about 75 mg to about 85 mg.

[0555] In some implementations, the subject is in a state of eating when the medication is administered.

[0556] In some implementations, the subjects are fasting when administered the medication.

[0557] The dosage and administration may be adjusted to provide adequate levels of the compounds disclosed herein or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health condition of the subject, the subject's age, weight and sex, diet, timing and frequency of administration, combination of drugs, sensitivity to response, and tolerance / response to the therapy.

[0558] In one aspect, this application relates to a method of treating and / or preventing SBMA, comprising administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to a subject in need in combination with one or more other bioactive agents.

[0559] In some embodiments, one or more additional bioactive agents are leuprorelin or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional bioactive agents are leuprorelin acetate.

[0560] In some embodiments, compound A or a pharmaceutically acceptable salt thereof and leuprolide acetate are administered to the subject simultaneously. In some embodiments, compound A or a pharmaceutically acceptable salt thereof and leuprolide acetate are administered to the subject sequentially.

[0561] In some implementations, compound A or a pharmaceutically acceptable salt thereof and one or more additional bioactive agents are administered to the subject at approximately the same time.

[0562] In some implementations, compound A or a pharmaceutically acceptable salt thereof, along with leuprolide or a pharmaceutically acceptable salt of leuprolide (e.g., leuprolide acetate), are administered to the subject at approximately the same time.

[0563] In some embodiments, "time proximity" means that the administration of compound A or a pharmaceutically acceptable salt thereof occurs within a period of time before or after the administration of one or more other bioactive agents, such that the therapeutic effects of compound A or a pharmaceutically acceptable salt thereof overlap with the therapeutic effects of one or more other bioactive agents. In some embodiments, the therapeutic effects of compound A or a pharmaceutically acceptable salt thereof completely overlap with the therapeutic effects of one or more other bioactive agents. In some embodiments, "time proximity" means that the administration of compound A or a pharmaceutically acceptable salt thereof occurs within a period of time before or after the administration of one or more other bioactive agents, such that there is a synergistic effect between compound A or a pharmaceutically acceptable salt thereof and one or more other bioactive agents. In some embodiments, the other bioactive agent is leuprolide or a pharmaceutically acceptable salt thereof. In some embodiments, the other bioactive agent is leuprolide acetate.

[0564] "Time proximity" can vary depending on various factors, including but not limited to the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent will be administered; the disease or symptom to be treated or improved; the treatment outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration. In some embodiments, "time proximity" means within 15 minutes, within 30 minutes, within one hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within two days, within three days, within four days, within five days, within six days, within one week, within two weeks, within three weeks, within four weeks, within six weeks, or within eight weeks. In some embodiments, multiple administrations of one therapeutic agent may occur in proximity to a single administration of another therapeutic agent. In some embodiments, time proximity may vary during a treatment cycle or within a dosing regimen.

[0565] Summary of Examples - Evaluation of AR PROTAC Degradants in Screening Layers Focuses on PolyQ-AR Degradation in Muscle

[0566] The screening layer is specifically designed to identify compounds with desired activity against polyQ-AR in cell types (myotubules) and tissues (muscle) severely affected by SBMA. Figure 10 Ultimately, compound A was found to improve the SBMA-related phenotype in a mouse disease model.

[0567] Example

[0568] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of the disclosure thereon. It should be further understood that various other implementations, modifications, and equivalents that may be conceived by those skilled in the art may be invoked without departing from the spirit of the disclosure and / or the scope of the appended claims.

[0569] Example 1 - Representative Method

[0570] Animal drug administration and tissue harvesting.

[0571] Six- to eight-week-old male C57Bl / 6 mice with free access to food and water were used. The compound was administered orally via tube feeding at the indicated dose using 5% dimethyl sulfoxide (DMSO) and 95% (2% Tween 80, PEG 400) as the medium. Unless otherwise specified, mice were euthanized by decapitation 24 hours after administration via isoflurane inhalation (2%–4%). The levator ani / bulbospongiosus muscle (LABC) was dissected and immediately rapidly frozen, and stored at -80°C prior to analysis. Compound exposure was measured in serum and muscle lysates.

[0572] In this study, male mice containing approximately 73 ± 14 copies of the full-length human AR ((hAR100Q)) with 100 CAG repeats in exon 1 (“hAR100Q mice”) were used. hAR100Q mice were obtained from mice (C57BL / 6J background) expressing heterozygous human normal-length AR100Q (AR100Q+ / -) under the control of the cytomegalovirus immediate early enhancer and the chicken β-actin (pCAGGS) promoter. These transgenic lines were preserved, and the population was expanded by breeding with C57BL / 6J (Jackson Laboratory) wild-type (WT) mice.

[0573] A total of 24 hAR100Q mice and 20 littermate controls were used in this study. Each genotype was divided into two groups of 10 mice each (control versus compound A), resulting in a total of four independent groups (WT control, WT compound A, hAR100Q control, and hAR100Q compound A). All mice began eating the control diet at 4 weeks of age. At 5 weeks of age, the treatment group was switched to the diet formulated with compound A, while the remaining mice continued to eat the control diet. Body weight was recorded weekly starting at 5 weeks of age.

[0574] Genotyping.

[0575] Mouse genotypes were determined by PCR using DNA extracted from mouse ear clips. Mouse ear DNA was extracted using the REDExtract-N-Amp tissue PCR kit. PCR was performed using the following primers: human AR transgene (forward 5'-CTTCTGGCGTGTGACCGGCG (SEQ ID NO: 2), reverse 5'-TGAGCTTGGCTGAATCTTCC (SEQ ID NO: 3)) and BC12 control (forward 5'-ATGGCGCAAGCCGGGAGAACA (SEQ ID NO: 4), reverse 5'-CCGGTTCAGGTACTCAGTCAT (SEQ ID NO: 5)).

[0576] Food preparation.

[0577] Compound A was formulated in rodent food (Purina #5015) at 100 parts per million (ppm). This dose level (100 ppm) is approximately 15 mg / kg for a mouse weighing 20 g and consuming 3 g of food daily. For the control diet, rodent food (Purina #5015) was regranulated in the same manner as the food formulated with compound A.

[0578] 4 claw grip.

[0579] Starting at 7 weeks of age, the force exerted by the forepaws alone or all four paws was measured weekly using a grip strength device. The device was placed on a sturdy, flat laboratory workbench, and the mesh of the device was used for all four paws. A single mouse grasped a metal mesh (for all four paws) and gently pulled it with the base of its tail to measure the maximum force it could maintain a grip. Six grip strength measurements were performed per mouse for all four paws.

[0580] treadmill.

[0581] The duration of running at an increasing speed until exhaustion was analyzed using a touchscreen treadmill. Individual mice ran on a treadmill with a graded acceleration program consisting of 10 m / min for the first 40 minutes, followed by 1 m / min increments every 10 minutes for 30 minutes, and finally 1 m / min increments every 5 minutes until exhaustion. Exhaustion was determined by 5 consecutive seconds or a total of 20 seconds of inactivity (staying on the treadmill bar at the start). Treadmill training was conducted for two days prior to the first week of testing. Day 1 consisted of 5 minutes at 8 m / min, while Day 2 consisted of 5 minutes at 8 m / min followed by 5 minutes at 10 m / min. All test events included a 1 m / min warm-up period leading to a 2-minute start speed.

[0582] Mouse AR ELISA.

[0583] The anti-androgen receptor rabbit polyclonal antibody (clone PG-21 (Millipore; 06-680)) was diluted in BupH carbonate-bicarbonate buffer (Thermo; 28382) to a concentration of 2 µg / mL and then incubated at 37°C. o Incubate 50 µL per well overnight at C20 to coat 96-well ELISA plates. Wash the plates four times with TBS-buffered saline (TBS) containing 0.1% Tween-20 (TBS-0.1%T) and block with TBS-T containing 3% bovine serum albumin for 3 hours at room temperature (200 µL / well). Dilute AR peptide standards (Creative Biomart; catalog number AR-9788H) and samples in 1% bovine serum albumin (BSA) / TBS-0.05%T. After the blocking period, wash the plates as above and add 50 µL of standards and samples. Incubate the plates at 4°C. o Incubate overnight at C with shaking. After incubation, allow the plate to acclimate to room temperature with shaking for 1 hour. Dilute the horseradish peroxidase (HRP) conjugated detection antibody (anti-AR antibody, clone EPR1535 (abcam; ab194196)) 1:15000 in 1% BSA / TBS-0.05%T and incubate with the sample by adding 50 µL to each well and shaking at room temperature for 2 hours. Wash the plate as above. Add the chemiluminescent substrate (ELISABright; Advansta; K-16025) to the plate (100 µL / well).

[0584] Cell lines.

[0585] Human embryonic kidney cells (T-REx™-293 cells) (Thermo Fisher Scientific - R71007) constitutively expressing tetracycline repressors, maintained in Durbeck modified Eagle medium (DMEM), supplemented with 10% heat-inactivated fetal bovine serum (26050088 Thermo Fisher Scientific), GlutaMAX (35050061 Thermo Fisher Scientific), and 1% penicillin / streptomycin (15140122 Thermo Fisher Scientific). AR and polyQ-AR were cloned downstream of the tetracycline operator gene array and stably integrated into T-REx™-293 cells. AR or polyQ-AR expression was induced with 1 µg / ml doxycycline.

[0586] Human AR56Q was amplified from a previously constructed plasmid containing polyQ-AR and Gibson was used. ® The assembly method cloned it into pLV-tetOn-luc2-res-turboGFP digested with Age / XhoI to generate plasmid 46. To construct the puromycin-selective form, Gibson was used. ® The assembly method involved ligating the XbaI AR56Q fragment from plasmid 46 into a lentiviral backbone amplified from template-2-px459. CAG repeat number was verified by Sanger sequencing. Second-generation lentivirus was generated by transfection with pSPAX2 and pMD2.G. AR56Q transfer plasmid growth medium was harvested and removed at 48 and 72 hours post-transfection, and subsequently concentrated by centrifugation. Titers were measured by real-time quantitative reverse transcription polymerase chain reaction.

[0587] Cells were maintained in bone growth medium (PromoCell #23160). Immortalized myoblasts with 56 CAG repeats and inducible human androgen receptor (hAR56Q) were constructed by lentiviral transduction with CMV-rtTA and TetO-AR56Q-T2A-puromycin (Mamchaoui, K. et al. Skeletal Muscle 1, 34 (2011)).

[0588] Myotube polyQ-AR HiBit.

[0589] Human myoblasts containing 56 polyQ-amplified androgen receptor (AR) markers labeled with HiBit protein were used as previously described (ACS Chem. Biol. 2018, 13, 2, 467-474). At 37... o Cells were cultured in skeletal muscle basal medium containing supplements (Promocell, #C23060) and 1% penicillin / streptomycin (ThermoFisher, #15070063) at C and 5% CO2 until plating. Prior to plating, 384-well plates were coated with 1:100 GelTrex (ThermoFisher, #1413201), diluted in DMEM / F12 (ThermoFisher, #11330032), and incubated at 37°C and 5% CO2. o Incubate at C for 1 to 2 hours. Then, before seeding myoblasts at a density of 8000 cells / well in 45 µL of muscle basal medium, aspirate the medium from the plate using a plate washer. The myoblasts are then incubated at 37°C. oIncubate overnight at C20°C. After overnight incubation, aspirate the culture medium from the plate using a plate washer and replace it with 45 µL of skeletal muscle differentiation medium (Promocell, #C23061) containing supplements. Allow to incubate at 37°C before compound treatment. o Differentiation was performed for four days under C4 conditions. Prior to treatment, the compound was diluted using Agilent Bravo by transferring 1 µL of the compound to 100 µL of skeletal muscle differentiation medium containing 10 µg / mL doxycycline in a 384-well deep-well plate. This intermediate plate was used to transfer 5 µL of the diluted compound to 45 µL of differentiated myotubes to produce a peak concentration of 1 µM doxycycline at 1 µg / mL for polyQ-AR induction. The myotubes were incubated for 24 hours for induction and compound treatment, and AR56Q was quantified using a Hibit (Promega) reading. The plate was removed from the incubator and allowed to reach room temperature for 45 minutes. Cells were then treated with 25 µL / well of lysis buffer containing 1:100 lysis substrate and 1:100 LgBit protein and allowed to incubate for 45 minutes, including shaking at 400 RPM for 10 minutes. The plate was then read on a plate reader under luminescent settings. Alamar Blue was used. TM (ThermoFisher, #A50100) Cell viability was measured in parallel on separate plates. Using 5 µL of Alamar Blue... TM Substrate plate and 37 o Incubate at C for 2 hours. Then remove the plates from the incubator and allow them to equilibrate to room temperature for 2 hours before reading on a plate reader at 560 / 590 (Ex / Em). All experiments were performed on separate dates in technical triplicate and biological duplicates.

[0590] Capillary immunoassay for AR.

[0591] Lysates of hiPSC-derived myotubes were prepared in a lysis buffer (25 nM HEPES, 50 mM sodium chloride, 1% NP-40, 1% SDS) supplemented with Halt protease inhibitor (78437 Thermo Fisher Scientific), Benzonase, and MgCl2 (1 mM final concentration). Lysates were removed by centrifugation at 4°C, and the supernatant was quantified using a BIO-RAD DC protein assay (5000112 BIO-RAD). AR and protein levels were quantified using an automated capillary immunoassay (ProteinSimple). AR and myosin levels were quantified and normalized to total protein.

[0592] Endogenous AR from mice, human AR100Q, and high molecular weight hAR100Q from hAR100Q mice were quantified by capillary immunoassay. Tissue lysates were prepared using antibodies against AR as described above and resolved by capillary electrophoresis (ProteinSimple). High molecular weight AR was quantified as the area under the curve (AUC) from 300 kDa to 600 kDa.

[0593] HEK293 PolyQ-AR High Content

[0594] HEK 293 PolyQ androgen receptor cell lines were cultured at 70% confluence. Cells were seeded in PDL-coated 384-well plates at a density of 10 K / well (333,333 cells / mL and 30 µL / well) in HEK PolyQ AR complete medium (DMEM (ThermoFisher Scientific 11965-084), 10% Tet-free FBS (ThermoFisher Scientific A47364-01), and 1% Penn Strep (ThermoFisher Scientific 15140122)). Cells were incubated overnight at 37°C and 5% humidity. The compound was diluted in 100% DMSO and diluted 1:3 for a 10-point concentration-response curve (CRC), with a maximum concentration of 0.06 mM. Next, 2.5 µL of the 100% compound was imprinted into 384-well plates using a Bravo liquid processor. Next, 50 µL of HEK PQ complete medium + 10 µg / mL doxycycline was added to a 2.5 µL imprint. Then, 3 µL of diluted compound plate with dox was added to the cell plate. The compound plates were run in triplicate. The final compound concentration was 300 nM in 0.5% DMSO and 1 µg / mL Dox. The plates were incubated overnight at 37°C. The next day, the medium was removed from the plates and replaced with 20 µL of 4% paraformaldehyde (PFA) (prepared in 1X PBS). The plates were incubated with PFA for 15 minutes and then washed three times with PBS. The plates were permeabilized with 0.5% Triton prepared in 1X PBS for 15 minutes and then blocked with 5% bovine serum albumin (BSA). The plates were incubated at room temperature with 5% BSA for one hour. The BSA was then removed from the plate and replaced with a primary androgen receptor antibody (D6F11 cell signaling 5135S) diluted 1:100 in PBS containing 0.1% BSA. The plate was sealed and incubated overnight at 4°C. The next day, the plate was washed three times with PBS. Next, 20 µL of secondary antibody (donkey anti-rabbit Alexa 647, Invitrogen A31573) diluted 1:1000 in 1x PBS and Hoechst 33352 dye (ThermoFisher Scientific H3570) diluted 1:500 were added to each well. The plate was incubated in the dark at room temperature for one hour. Finally, the plate was washed three times with 1x PBS and then sealed with a black seal to protect from light. The plate was imaged using a 20x objective on a CX7 PRO (Thermos Fisher Scientific). Two channels were acquired per well: Hoechst 33342 and Alexa 488, with six fields of view per well.Images were analyzed by segmenting cell nuclei using Hoechst positive signals. AR degradation was then measured by determining the average intensity of AR in individual nucleus and cytoplasmic compartments.

[0595] AR activating assay.

[0596] A stable cell line of MDA-MB-453 (MDA-MB-453 ARE-luc) was used for AR activating assays. These cells constitutively express the firefly luciferase reporter gene under the control of androgen receptor responsive elements. MDA-MB-453 ARE-luc cells were cultured in RPMI medium (Thermo Fisher Scientific) supplemented with 5% charcoal-dextran-treated fetal bovine serum and maintained at 37°C in a 5% CO2 incubator. On day 0, cells were cultured at 5 × 10⁶ cells / year. 6 Cells were seeded at a density in 96-well plates. To prevent interference from serum androgens during the AR activating assay, cells were cultured in FBS-free, phenol red-free RPMI medium. On day 1, cells were treated with the compound to establish a concentration-response curve (CRC). The compound was administered at its maximum concentration of 300 nM at a half-log dilution. The synthetic AR agonist R1881 was used as a positive control at its maximum concentration of 30 nM and at a half-log dilution. The E3 ligase inhibitor pomalidomide was included in each well next to the compound at a concentration ten times that of the treated compound. On day 2, the medium was removed, and luminescence data were obtained using a Bright Glo assay (Promega, catalog number E2620) with 50 μL Bright Glo buffer / well. The luminescence signal was recorded using a plate reader, and the activating effect was calculated as a percentage using the following formula: Activating effect (%) = (Chemical luminescence signal / Maximum signal of R1881 at 30 nM) * 100.

[0597] Myotube high content.

[0598] On day 0, immortalized myoblasts with inducible polyQ-AR (described in the “Cell Line” above) cells were cultured in Geltrex-coated 96-well plates at a rate of 4 × 10⁶ cells / well. 6 Cells were seeded at a density of 100 cells / plate in myoblast basal medium (Promocell C-23060) supplemented with 1% penicillin-streptomycin (Pen Strep) antibiotic. The plates were then incubated overnight at 37°C in a 5% CO2 environment. When 100% confluence was reached (Day 1), the myoblast medium was aspirated and replaced with myotube differentiation medium (Promocell C-23061). Cells were cultured in this differentiation medium for 6 days, with the medium changed every three days.

[0599] On day 6 of differentiation, the compound and doxycycline (1 µg / ml) diluted in 100% dimethyl sulfoxide (DMSO) were added to the myotubes. The plates were then incubated at 37°C for 24 hours. On day 7, the medium was removed from the plates and replaced with 50 μL of 4% paraformaldehyde (PFA) prepared in 1X phosphate-buffered saline (PBS). The plates were incubated with PFA for 15 minutes and then washed three times with PBS. Subsequently, the myotubes were permeabilized with 1X PBS containing 0.5% Triton X-100 for 15 minutes and then blocked with 5% bovine serum albumin (BSA) (Thermofisher, #37520) at room temperature for one hour. After blocking, the plates were incubated overnight at 4°C with primary antibodies: a 1:100 dilution of androgen receptor antibody (D6F11 cell signaling 5135S) and a 1:200 dilution of desmin antibody (Thermofisher, MA1-22150) in PBS containing 0.1% BSA. The next day, the plates were washed three times with PBS and then incubated for one hour at room temperature in the dark with secondary antibodies: goat anti-mouse 647 (A21236) for desmin and goat anti-rabbit Alexa 488 for AR (A11034), both diluted 1:1000 in 1X PBS. Additionally, Hoechst 33342 (ThermoFisher Scientific H3570) diluted 1:500 was added to each well. The plates were then washed three times with 1X PBS, sealed with black caps to protect from light, and imaged using a CX7 PRO microscope equipped with 20x objectives. Three channels were acquired per well: Hoechst 33342 and Alexa 488 and 647, with each well comprising six fields of view. Image analysis involved segmenting cell nuclei using Hoechst positive signals and selecting myotubes using desmin-positive regions. Degradation was quantified by determining the mean intensity of AR in individual nuclei and cytoplasmic compartments within the desmin-positive regions (myotubes).

[0600] Myotube differentiation.

[0601] Control and SBMA hiPSCs were differentiated into myotubes using a skeletal muscle differentiation kit (Amsbio) as previously described (Caron, L. et al. 2016, STEM CELLS Transl. Med. 5, 1145-1161). hiPSCs were dissociated into single cells using Accutase and seeded at a density of 200,000 cells / plate in skeletal muscle induction medium (SKM01, AMSBIO) with SBMA hiPSCs in 10 cm gel-coated culture plates. The medium was changed every other day until cell confluence (approximately 7 days). The resulting myoblast precursor cells were then dissociated into single cells using Accutase and re-seeded at 35,000 cells / mL in 24-well tissue culture plates coated with Matrigel gel (500 µL of cells) in skeletal muscle myoblast medium (SKM02, AMSBIO). Half of the medium was changed every other day until myoblast confluence (approximately 7 days). The culture medium was then replaced with myotube medium (SKM03, ASMBIO). The medium was changed every other day until myotube formation was confirmed by microscopy. On day 20 of differentiation, the myotubes were treated with a compound diluted in DMSO (equivalent to 6 days of SKM03 medium) to bring the final DMSO concentration in the SKM03 medium to 0.01%. Twenty-four hours later, cells were lysed in Pierce RIPA buffer (catalog number 89900, ThermoFisher) supplemented with 1x Halt protease inhibitor mixture (catalog number 87786, ThermoFisher), 1 mM MgCl2, and 1 µL Benzonase nuclease. AR protein was measured by capillary electrophoresis.

[0602] Example 2 - Identification of compounds for treating SBMA

[0603] 132 compounds (DCs) with potent activity in VCaP cells were evaluated in two orthogonal in vitro polyQ-AR degradation assays. 50 0.032 nM - 2.5 nM; Figure 1 The degradation of HiBit-labeled polyQ-AR was measured in human muscle tubes using Nano-Glo HiBit lysis assay. Figure 2A ) and assessed the degradation of unlabeled polyQ-AR by high-content imaging in HEK293 cells ( Figure 2B ).like Figure 2A and Figure 2B As shown, several compounds exhibited similar potency to compound A. In vitro profiling (DC) based on AR and polyQ-AR measurements... 50 / D max), 95 of the 132 compounds were selected for in vivo screening ( Figure 2C and Figure 2D ).

[0604] The in vivo degradation of endogenous analgesics (AR) of 95 compounds was evaluated in mouse levator ani / bulbospongiosus muscle (LABC) using a PO dose of 30 mg / kg (see Example 1). The AR degradation rates of these 95 compounds ranged from 0% to 85% in mouse LABC. Of the 95 compounds evaluated, 77 failed to induce more than 50% AR degradation in muscle. Figure 3 These results indicate that in vitro DCs in various assays... 50 / D max There was no correlation between this and in vivo AR degradation observed in muscle (Table 1).

[0605] Table 1. DCs from AR degradation assays in VCaP (AR), HEK293 (polyQ-AR), and myotubular cells (polyQ-AR) 50 With D max The correlation matrix between them, and the degradation observed in the LABC muscle of C57Bl / 6 mice using the compound at a dose of 30 mg / kg.

[0606]

[0607] Twenty compounds were selected for further in vivo and in vitro characterization. In vivo potency at multiple dose levels was evaluated to establish the pharmacokinetic (PK / PD) relationship between exposure and AR degradation in LABC muscle. Subacute adverse events were assessed for compounds exhibiting effective dose-response PK / PD (i.e., higher doses induced more AR degradation). Specifically, compounds that induced weight loss 7 days after administration (30 mg / kg PO) were disqualified. Other compounds were not considered due to unfavorable in vitro ADMET activity (compound C: 50% hepatotoxicity at 1 µM; compound D: hERG inhibition <10 µM) or poor oral bioavailability in non-human primates (compound E). Of the screened compounds, only compounds A and B remained as suitable in vivo candidates.

[0608] The chronic and progressive symptoms of SBMA are driven by the androgen-dependent toxicity of polyQ-AR. Unbound by theory, the ideal compound for treating SBMA would have minimal AR agonist activity (e.g., not inducing androgen-dependent AR activity) and would prevent AR translocation to the nucleus by mediating its degradation. To separate the AR agonist activity of a compound from its AR degradation, agonism was assessed using MDA-MB-453 cells engineered with an AR luciferase reporter gene in the presence of pomalidomide to block the compound's binding to CRBN (see Example 1). EC50 of compounds A and B 50 69 nM and 37 nM respectively Figure 4A ). In E max Below, compound A showed slightly lower agonistic activity relative to R1881 (<40%) than compound B (>40%). Figure 4A AR in the nuclear compartment was measured in the presence of the compound by high-content imaging in myotubes overexpressing polyQ-AR (see Example 1). The mean Da in the myotube nucleus was achieved by compound A. max It is approximately 40%. In contrast, the average D of compound B is... max The changes were significant, and on average, indicated an increase in nuclear polyQ-AR compared to DMSO control cells. Figure 4B and Figure 4C Therefore, although compound B reduced the total polyQ-AR signal in myotubes (data not shown), it had more AR available to mediate transcription in the nucleus than in cells treated with compound A.

[0609] Human induced pluripotent stem cells (hiPSCs) from SBMA patients can be used to generate myotubes in vitro (Caron, L. et al. 2016, Stem Cells Transl. Med. 5, 1145–1161). This provides a human cell model associated with SBMA. To confirm the pharmacology of compound A in disease-associated cells with the correct genetic background, myotubes were derived from hiPSCs from two independent SBMA patients and treated with compound A.

[0610] Between the two donor hiPSC systems, DC was used 50 and D max Compound A, at concentrations of 0.6–0.8% and 83%–96%, was observed to reduce polyQ-AR in SBMA hiPSC-myotubules in a concentration-dependent manner. Figure 5A Compound F (the E3 inactive form of compound A) does not induce polyQ-AR degradation. Figure 5BTherefore, compound A induces the degradation of polyQ-AR in disease-associated cells from SBMA patients in a CRBN-dependent manner.

[0611] Example 3 - Efficacy of Compound A in SBMA Mouse Model

[0612] In the SBMA mouse model used here (hereinafter referred to as hAR100Q mice), which also expresses endogenous mouse AR, approximately 73 ± 14 copies of the full-length human AR (hAR100Q) with 100 CAG repeats are driven by the pCAGGS promoter (Chivet, M. et al. 2020, Cells 9, 325). Heterologous expression of hAR100Q leads to muscle atrophy, motor deficits, and premature death (Chivet, M. et al. 2020, Cells 9, 325). Symptoms begin to appear as early as 8 weeks of age and progressively worsen until 13 to 14 weeks, at which point the mice are euthanized due to extreme immobility. In this study, male hAR100Q mice and littermate controls (10 mice in each group) were fed either a carrier diet or a diet formulated with compound A at a dose of approximately 15 mg / kg. Due to the fragile nature of this disease model, dietary administration was used instead of PO administration. The diet formulated with compound A was introduced at 5 weeks of age. In addition to weekly weight measurements, behavioral assessments were used to evaluate the mice, including weekly grip strength measurements and a forced treadmill test at 11 weeks of age.

[0613] Compared to hAR100Q mice fed with a food medium, the food formulated with compound A rescued the weight loss of hAR100Q mice over time. Figure 6B ), but it has no effect on WT's littermates ( Figure 6C Starting at week 9, grip strength in hAR100Q mice decreased weekly. Compound A slowed the decline in grip strength and the rate of decline. Figure 7A Throughout the study period, grip strength was similar among littermates treated with both the medium and compound A. Figure 7B Muscle endurance was tested at week 11 using a forced treadmill test. Compared to their WT littermates, hAR100Q mice covered a significantly shorter distance on the treadmill. Figure 7C However, hAR100Q mice fed with food formulated with compound A performed as well as their WT littermates. No difference was observed between WT littermates fed the medium and those fed compound A. Figure 7C ).

[0614] To assess AR degradation at the 11-week time point, a parallel hAR100Q mouse cohort was maintained. The hAR100Q mice in this tissue cohort were fed the same diet as mice that underwent muscle strength and endurance tests and were euthanized at 11 weeks of age.

[0615] Endogenous mouse AR and monomeric hAR100Q were reduced by 77% and 70%, respectively. Figure 8A , Figure 8B , Figure 8C The reduction in total hAR100Q was not statistically significant. Figure 8A , Figure 8D ).

[0616] Compound A induced the degradation of polyQ-AR in the quadriceps femoris muscle of AR100Q mice.

[0617] 40%-60% of AR / polyQ-AR is degraded in the quadriceps femoris muscle.

[0618] The decrease in high molecular weight substances varied considerably, but showed a decreasing trend. See the results below. Figure 8E , Figure 8F , Figure 8G and Figure 8H .

[0619] Compared to hAR100Q mice fed a carrier for 96 days, hAR100Q mice fed a diet formulated with compound A had an increased median lifespan of 151 days. Figure 9 Lifespan is considered to be the number of days from birth to the date of euthanasia. In this study, hAR100Q mice were euthanized when they were considered to be in a near-death state. Unbound by theory, these data confirm that polyQ-AR degradation mediated by compound A is a potential therapeutic for SBMA.

[0620] Example 4 - Compound A induces AR degradation in the presence of physiologically relevant concentrations of androgens.

[0621] Compared to healthy individuals, SBMA subjects had normal levels of androgens. (Lancet Neurol. Feb. 2011;10(2):140-7. doi: 10.1016 / S1474-4422(10)70321-5. E-published Jan. 6, 2011. PMID: 21216197; PMCID: PMC3056353.) To simulate the in vivo conditions of SBMA subjects, experiments were conducted to test the binding of androgens (e.g., dihydrotestosterone (DHT)) to compound A in competition for AR binding. Figure 11 Compound A has a DC concentration of 5.9 nM in hiPSC myotubules in the presence of DHT at 500 pM.50 In the absence of any DHT (0 pM), the DC of compound A is... 50 The concentration was increased to 0.5 nM. These results show that the presence of natural androgens alters the pharmacology, but compound A still degrades target proteins in hiPSC myotubules.

[0622] Example 5 - Global proteomics of SBMA hiPSC-myotubes indicates a single novel substrate: PDE6D

[0623] Global proteomics analysis in hiSPC-myotubes revealed that compound A was specific for AR. Compared to the control, compound A degraded polyQ-AR, while the E3 inactive compound (compound F) did not degrade AR. Figure 12A Of the approximately 7,600 proteins detected, only one novel substrate (off-target substrate) (PDE6D) was identified in the myotubules of compound A. Figure 12B Western blot analysis confirmed a reduction of approximately 50% in PDE6D (data not shown). PDE6D is not a novel substrate for compound F, which is a modified form of compound A that does not bind to the CRBN E3 ubiquitin ligase. Figure 12C ).

[0624] Example 6 - PK / PD in mouse muscle

[0625] Compound A degrades AR in muscle tissue ( Figure 13A and Figure 13B ).

[0626] The free fraction of compound A in mice was low (plasma = 0.44%).

[0627] Approximately 10 mg / kg achieves approximately 50% AR degradation.

[0628] AR levels in the LABC muscles return to baseline within approximately 48 to 72 hours. Figure 13C ).

[0629] Equivalent form

[0630] Although the invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations will be apparent to those skilled in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the invention.

[0631] List of implementation plans

[0632] Aspects of this disclosure are further described with reference to the following numbered embodiments:

[0633] 1. A method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0634] Or, or a pharmaceutically acceptable salt thereof.

[0635] 2. Compound A,

[0636] Or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0637] 3. Compound A,

[0638] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0639] 4. A method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0640] Or, or a pharmaceutically acceptable salt thereof.

[0641] 5. Compound A,

[0642] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0643] 6. Compound A,

[0644] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0645] 7. A method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject:

[0646] Or, or a pharmaceutically acceptable salt thereof.

[0647] 8. Compound A,

[0648] Or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0649] 9. Compound A,

[0650] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0651] 10. A method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0652] Or, or a pharmaceutically acceptable salt thereof.

[0653] 11. Compound A,

[0654] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0655] 12. Compound A,

[0656] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0657] 13. A method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0658] Or, or a pharmaceutically acceptable salt thereof.

[0659] 14. Compound A,

[0660] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0661] 15. Compound A,

[0662] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0663] 16. A method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A:

[0664] Or, or a pharmaceutically acceptable salt thereof.

[0665] 17. Compound A,

[0666] Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

[0667] 18. Compound A,

[0668] The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

[0669] 19. The method, compound, or use as described in any one of embodiments 7 to 12 or 16 to 18, wherein the SBMA symptoms are fatigue, muscle spasms, weakness in the limbs, difficulty chewing, difficulty swallowing, difficulty speaking, diminished deep tendon reflexes, lack of pathological reflexes, diminished leg vibration sensation, erectile dysfunction, decreased fertility, gynecomastia, testicular atrophy, glucose resistance, hyperlipidemia, fatty liver disease, or a combination thereof.

[0670] 20. The method, compound, or use as described in any one of embodiments 1 to 19, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0671] 21. The method, compound, or use as described in any one of embodiments 1 to 20, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject in tablet form.

[0672] 22. The method, compound, or use as described in any one of embodiments 1 to 20, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally as a solution to the subject.

[0673] 23. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 5 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0674] 24. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 50 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0675] 25. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 5 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0676] 26. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 10 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0677] 27. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 15 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0678] 28. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 20 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0679] 29. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 25 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0680] 30. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0681] 31. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 25 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0682] 32. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 50 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0683] 33. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 75 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0684] 34. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 100 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0685] 35. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 125 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0686] 36. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0687] 37. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 175 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0688] 38. The method, compound, or use as described in any one of embodiments 1 to 22, wherein about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0689] 39. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 25 mg to about 75 mg, about 30 mg to about 80 mg, about 35 mg to about 85 mg, about 40 mg to about 90 mg, about 45 mg to about 95 mg, about 50 mg to about 100 mg, about 55 mg to about 105 mg, about 60 mg to about 110 mg, about 65 mg to about 115 mg, about 70 mg to about 120 mg, or about 75 mg to about 125 mg.

[0690] 40. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 30 mg to about 75 mg, about 35 mg to about 80 mg, about 40 mg to about 85 mg, about 45 mg to about 90 mg, about 50 mg to about 95 mg, about 55 mg to about 100 mg, about 60 mg to about 105 mg, about 65 mg to about 110 mg, about 70 mg to about 115 mg, or about 75 mg to about 120 mg.

[0691] 41. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 35 mg to about 75 mg, about 40 mg to about 80 mg, about 45 mg to about 85 mg, about 50 mg to about 90 mg, about 55 mg to about 95 mg, about 60 mg to about 100 mg, about 65 mg to about 105 mg, about 70 mg to about 110 mg, or about 75 mg to about 110 mg.

[0692] 42. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 40 mg to about 75 mg, about 45 mg to about 80 mg, about 50 mg to about 85 mg, about 55 mg to about 90 mg, about 60 mg to about 95 mg, about 65 mg to about 100 mg, about 70 mg to about 105 mg, or about 75 mg to about 110 mg.

[0693] 43. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 45 mg to about 75 mg, about 50 mg to about 80 mg, about 55 mg to about 85 mg, about 60 mg to about 90 mg, about 65 mg to about 95 mg, about 70 mg to about 100 mg, or about 75 mg to about 105 mg.

[0694] 44. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0695] 45. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

[0696] 46. ​​The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 55 mg to about 75 mg, about 60 mg to about 80 mg, about 65 mg to about 85 mg, about 70 mg to about 90 mg, or about 75 mg to about 95 mg.

[0697] 47. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 60 mg to about 75 mg, about 65 mg to about 80 mg, about 70 mg to about 85 mg, or about 75 mg to about 90 mg.

[0698] 48. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 65 mg to about 75 mg, about 70 mg to about 80 mg, or about 75 mg to about 85 mg.

[0699] 49. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 200 mg to about 500 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 350 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.

[0700] 50. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 250 mg to about 500 mg, about 250 mg to about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, or about 250 mg to about 300 mg.

[0701] 51. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, or 300 mg to about 350 mg.

[0702] 52. The method, compound, or use as described in any one of embodiments 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 350 mg to about 500 mg, about 350 mg to about 450 mg, about 350 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg.

[0703] 53. The method, compound, or use as described in any one of embodiments 1 to 52, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject once a day, once every two days, once every three days, or once every four days.

[0704] 54. The method, compound, or use as described in any one of embodiments 1 to 53, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0705] 55. The method, compound, or use as described in any one of embodiments 1 to 54, wherein the subject is in an eating state at the time of administration.

[0706] 56. The method, compound, or use as described in any one of embodiments 1 to 54, wherein the subject is in a fasting state at the time of administration.

Claims

1. A method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject: Or, or a pharmaceutically acceptable salt thereof.

2. Compound A, Or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

3. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

4. A method for treating spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A: Or, or a pharmaceutically acceptable salt thereof.

5. Compound A, Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

6. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

7. A method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering an effective amount of compound A to the subject: Or, or a pharmaceutically acceptable salt thereof.

8. Compound A, Or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering an effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

9. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises an effective amount of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

10. A method for treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A: Or, or a pharmaceutically acceptable salt thereof.

11. Compound A, Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating symptoms of spinal bulbar muscular atrophy (SBMA) in a subject in need, wherein the method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

12. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

13. A method for treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A: Or, or a pharmaceutically acceptable salt thereof.

14. Compound A, Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

15. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

16. A method for treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, comprising administering to the subject about 1 mg to about 500 mg of compound A: Or, or a pharmaceutically acceptable salt thereof.

17. Compound A, Compound A or a pharmaceutically acceptable salt thereof, used in a method of treating or preventing symptoms of spinal bulbar muscular atrophy (SBMA) in a subject of need, wherein said method comprises administering to the subject about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof.

18. Compound A, The use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of symptoms of spinal bulbar muscular atrophy (SBMA), wherein the medicament comprises about 1 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof, and the medicament is administered to a subject in need.

19. The method, compound, or use according to any one of claims 7 to 12 or 16 to 18, wherein the SBMA symptoms are fatigue, muscle spasms, weakness in the limbs, difficulty chewing, difficulty swallowing, difficulty speaking, diminished deep tendon reflexes, lack of pathological reflexes, diminished leg vibration sensation, erectile dysfunction, decreased fertility, gynecomastia, testicular atrophy, glucose resistance, hyperlipidemia, fatty liver disease, or a combination thereof.

20. The method, compound, or use as described in any one of claims 1 to 19, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

21. The method, compound, or use as claimed in any one of claims 1 to 20, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject in tablet form.

22. The method, compound, or use as claimed in any one of claims 1 to 20, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally as a solution to the subject.

23. The method, compound, or use as described in any one of claims 1 to 22, wherein about 5 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

24. The method, compound, or use according to any one of claims 1 to 22, wherein about 50 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

25. The method, compound, or use according to any one of claims 1 to 22, wherein about 5 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

26. The method, compound, or use according to any one of claims 1 to 22, wherein about 10 mg to about 350 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

27. The method, compound, or use according to any one of claims 1 to 22, wherein about 15 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

28. The method, compound, or use according to any one of claims 1 to 22, wherein about 20 mg to about 250 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

29. The method, compound, or use according to any one of claims 1 to 22, wherein about 25 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

30. The method, compound, or use according to any one of claims 1 to 22, wherein about 30 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

31. The method, compound, or use according to any one of claims 1 to 22, wherein about 25 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

32. The method, compound, or use as described in any one of claims 1 to 22, wherein about 50 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

33. The method, compound, or use as described in any one of claims 1 to 22, wherein about 75 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

34. The method, compound, or use as described in any one of claims 1 to 22, wherein about 100 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

35. The method, compound, or use as described in any one of claims 1 to 22, wherein about 125 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

36. The method, compound, or use as described in any one of claims 1 to 22, wherein about 150 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

37. The method, compound, or use as described in any one of claims 1 to 22, wherein about 175 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

38. The method, compound, or use as described in any one of claims 1 to 22, wherein about 200 mg of compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

39. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 25 mg to about 75 mg, about 30 mg to about 80 mg, about 35 mg to about 85 mg, about 40 mg to about 90 mg, about 45 mg to about 95 mg, about 50 mg to about 100 mg, about 55 mg to about 105 mg, about 60 mg to about 110 mg, about 65 mg to about 115 mg, about 70 mg to about 120 mg, or about 75 mg to about 125 mg.

40. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 30 mg to about 75 mg, about 35 mg to about 80 mg, about 40 mg to about 85 mg, about 45 mg to about 90 mg, about 50 mg to about 95 mg, about 55 mg to about 100 mg, about 60 mg to about 105 mg, about 65 mg to about 110 mg, about 70 mg to about 115 mg, or about 75 mg to about 120 mg.

41. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 35 mg to about 75 mg, about 40 mg to about 80 mg, about 45 mg to about 85 mg, about 50 mg to about 90 mg, about 55 mg to about 95 mg, about 60 mg to about 100 mg, about 65 mg to about 105 mg, about 70 mg to about 110 mg, or about 75 mg to about 110 mg.

42. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 40 mg to about 75 mg, about 45 mg to about 80 mg, about 50 mg to about 85 mg, about 55 mg to about 90 mg, about 60 mg to about 95 mg, about 65 mg to about 100 mg, about 70 mg to about 105 mg, or about 75 mg to about 110 mg.

43. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 45 mg to about 75 mg, about 50 mg to about 80 mg, about 55 mg to about 85 mg, about 60 mg to about 90 mg, about 65 mg to about 95 mg, about 70 mg to about 100 mg, or about 75 mg to about 105 mg.

44. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

45. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 50 mg to about 75 mg, about 55 mg to about 80 mg, about 60 mg to about 85 mg, about 65 mg to about 90 mg, about 70 mg to about 95 mg, or about 75 mg to about 100 mg.

46. ​​The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 55 mg to about 75 mg, about 60 mg to about 80 mg, about 65 mg to about 85 mg, about 70 mg to about 90 mg, or about 75 mg to about 95 mg.

47. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 60 mg to about 75 mg, about 65 mg to about 80 mg, about 70 mg to about 85 mg, or about 75 mg to about 90 mg.

48. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 65 mg to about 75 mg, about 70 mg to about 80 mg, or about 75 mg to about 85 mg.

49. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 200 mg to about 500 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 350 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.

50. The method, compound, or use of any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 250 mg to about 500 mg, about 250 mg to about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, or about 250 mg to about 300 mg.

51. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, or 300 mg to about 350 mg.

52. The method, compound, or use according to any one of claims 1 to 22, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in one of the following amounts: about 350 mg to about 500 mg, about 350 mg to about 450 mg, about 350 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg.

53. The method, compound, or use as described in any one of claims 1 to 52, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject once a day, once every two days, once every three days, or once every four days.

54. The method, compound, or use as described in any one of claims 1 to 53, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

55. The method, compound, or use as claimed in any one of claims 1 to 54, wherein the subject is in an eating state at the time of administration.

56. The method, compound, or use as described in any one of claims 1 to 54, wherein the subject is in a fasting state at the time of administration.

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