Methods and compositions for treating Huntington's disease and its symptoms

Abstract

Methods and compositions are disclosed for treating patients with Huntington's disease or for treating symptoms of Huntington's disease. The methods include administering to the patient an effective amount of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM. In some embodiments, the GRM is dazcorilant. In some embodiments, the GRM is zabaccorilant. In some embodiments, the GRM is administered orally. In some embodiments, the GRM is administered daily. In other embodiments, the GRM is administered on a schedule, such as every other day, every three days, once a week, or other dosing schedules. Symptoms of Huntington's disease that may be treated by the methods include, but are not limited to, motor symptoms (e.g., muscle weakness, abnormal posture, difficulty walking, difficulty swallowing) and neurological or psychological symptoms (e.g., seizures, amnesia, confusion, speech disorders, delirium, depression, anxiety).

Description

[Technical Field]

[0001] Huntington's disease (HD), also known as Huntington's chorea, is a genetic neurodegenerative disorder in which patients exhibit motor and cognitive impairment, psychiatric disorders, muscle wasting, and metabolic dysfunction. As defined by the World Federation of Neurology, chorea is characterized by excessive, spontaneous movements that are irregularly timed, nonrepetitive, randomly distributed, and episodic in nature. These movements are called "choreic" movements. [Background technology]

[0002] HD is caused by an excess number of CAG repeats (35+) in the huntingtin gene. This increase in CAG repeats results in a mutant huntingtin protein (mHtt) that has acquired toxic functions and partially lost its native function. This mutant protein, mHtt, promotes pathological interactions and aggregation in the brain, leading to cellular dysfunction and ultimately neuronal death. mHtt aggregates are the neuropathological hallmark of the disease. Patients with HD experience progressive deterioration of cognitive, motor, and metabolic impairments. HD is a terminal disease, typically resulting in death within approximately 15 to 30 years from the onset of initial symptoms.

[0003] Current treatments for HD are primarily symptomatic and limited to treatments to help patients cope with the disease and to address the psychological aspects of living with a progressive and fatal neurological disease. Tetrabenazine may be prescribed to reduce the frequency or severity of sudden or abnormal chorea associated with HD. Medications such as haloperidol, risperidone, chlorpromazine, and amantadine, although not approved for such use, may also be used in an attempt to reduce the frequency or severity of such unwanted chorea associated with HD. Antidepressants or anti-anxiety medications may be prescribed to alleviate the depression or anxiety experienced by many patients with HD. Several HD-related symptoms, including neurodegeneration, cognitive decline, muscle atrophy, and metabolic dysfunction, are associated with high levels of endogenous glucocorticoids. 1-3 The R6 / 2 mouse strain, the most commonly used HD model, exhibits elevated glucocorticoid levels, mHtt aggregates, and various motor symptoms. 4-6 .

[0004] The glucocorticoids cortisol (e.g., in humans) and corticosterone (e.g., in rodents) are steroid hormones produced in the adrenal glands and have a wide range of effects throughout the body. Cortisol and corticosterone act through binding to the glucocorticoid receptor (GR). Mifepristone (RU486), the most commonly used GR modulator (GRM), is not specific to GR and also has affinity for other nuclear steroid receptors, such as the progesterone receptor (PR) and the androgen receptor (AR). This lack of selectivity for GR can cause side effects related to PR or AR activity when administered for use against GR, or side effects related to GR activity when administered for use against PR or AR.

[0005] Thus, there is a need in the art for additional effective treatments for HD. Where such treatments relate to cortisol activity in humans, GRMs that are more selective for GR than mifepristone are desirable. Summary of the Invention [Problem to be solved by the invention]

[0006] Disclosed herein are novel methods for treating Huntington's disease (HD) and alleviating symptoms associated with HD. The methods include administering to a subject an effective amount of a glucocorticoid receptor modulator (GRM) effective to treat a patient suffering from HD, and administering to the subject an effective amount to treat patient symptoms associated with HD, including, but not limited to, motor symptoms, neurological symptoms, and psychological symptoms.

[0007] Motor symptoms include, but are not limited to, involuntary jerking movements (convulsions), involuntary writhing movements (chorea), muscle contractions or rigidity (dystonia), tremors, slow or abnormal eye movements, muscle weakness, decreased grasp, gait disturbances (i.e., difficulty walking), balance disturbances, swallowing disturbances, breathing disturbances, abnormal posture, decreased ability to stand upright, decreased ability to maintain head position, speech disturbances, and other motor symptoms. Impairment is measured in comparison to a baseline motor activity performance (e.g., before the onset of HD symptoms or at the time of initial diagnosis of HD symptoms).

[0008] Neurological and psychological symptoms include, but are not limited to, epileptic seizures, amnesia, other memory losses, confusion, speech disturbances, poor concentration, slowed comprehension, delirium, hallucinations, paranoia, depression, anxiety, apathy, sudden or episodic mood swings, and other neurological or psychological symptoms. Impairment is determined by comparison with a baseline performance or level of neurological or psychological activity or symptoms (e.g., before the onset of HD symptoms or at the time of initial diagnosis of HD symptoms).

[0009] In one embodiment, the GRM is a selective GRM (SGRM), exhibiting activity against GR but little or no activity against other steroid hormone receptors (e.g., little or no activity against PR or AR). In one embodiment, the GRM is a non-steroidal compound comprising a heteroaryl ketone-fused azadecalin structure, the heteroaryl ketone-fused azadecalin structure being one of those described and disclosed in U.S. Patent No. 8,859,774. In one embodiment, the GRM is a non-steroidal compound comprising an octahydro-fused azadecalin structure, the octahydro-fused azadecalin structure being one of those described and disclosed in U.S. Patent No. 10,047,082.

[0010] In one embodiment, the GRM is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (referred to as "dazcorilant" or "CORT113176"), which comprises a heteroaryl ketone-fused azadecalin structure having the following structure:

[0011] [ka]

[0012] In one embodiment, the GRM is a compound comprising an octahydro-fused azadecalin structure, having the following structure: ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (also referred to as zavacorilant, or "CORT125329"). The entire contents of U.S. Patent Nos. 8,859,774 and 10,047,082 are incorporated herein by reference.

[0013] [ka]

[0014] In one embodiment, GRM is orally administered to a patient. Treatment of GRM for HD or for HD symptoms may involve daily GRM administration (e.g., once daily, twice daily, or other daily administration schedules) or intermittent GRM administration (e.g., once daily, once every three days, twice weekly, or other administration schedules). In one embodiment, an effective amount of GRM is a dose of about 1 to about 100 milligrams per kilogram (mg / kg). For example, a GRM dose for daily GRM administration to treat HD or to treat symptoms of HD is a dose of about 1 to about 100 mg / kg / day (mg / kg / day), or about 3 mg / kg / day to about 75 mg / kg / day, or about 5 mg / kg / day to about 50 mg / kg / day. In certain embodiments, the daily dose of GRM is about 5 milligrams per day (mg / day) to about 3000 mg / day, or about 10 mg / day to about 2500 mg / day, or about 20 mg / day to about 2250 mg / day, or about 30 mg / day to about 2000 mg / day, or about 40 mg / day to about 1750 mg / day, or about 50 mg / day to about 1500 mg / day, or about 75 mg / day to about 1000 mg / day, or about 100 mg / day to about 750 mg / day, or about 150 mg / day to about 500 mg / day. GRM therapy may be administered chronically as needed; thus, such therapy may be for a period of one year, or for a period of several years, or may be administered for many years. In certain embodiments, GRM treatment involves administration of GRM for at least 1 to about 80 weeks, or longer. The GRM can be administered in conjunction with other drugs or treatments administered to a patient with HD, or while the patient with HD is receiving other drugs or treatments for HD or its symptoms.

[0015] The methods of the present invention provide improved methods for treating HD and for treating the symptoms of HD. [Brief explanation of the drawings]

[0016] [Figure 1A] Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Forelimb grip strength was measured over time in male mice. Data are presented as mean + standard error of mean (SEM) and analyzed by three-way analysis of variance or mixed-effects model. Each time point was analyzed by two-way analysis of variance. Results of Tukey's multiple comparisons are shown as *p<0.05, and the symbol "+" indicates a comparison between WT-Veh and HD-CORT113176. [Figure 1B] Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Hindlimb grip strength was measured over time in male mice. Data are presented as mean ± standard error of mean (SEM) and analyzed by three-way analysis of variance or mixed-effects model. Each time point was analyzed using two-way analysis of variance, and the results of Tukey's multiple comparisons are shown as ***p<0.001 and ***p<0.0001. (The symbol "*" represents the comparison between WT-Veh and HD-Veh, the symbol "$" represents the comparison between WT-CORT113176 and HD-Veh, and the symbol "#" represents the comparison between HD-CORT113176 and HD-Veh.) [Figure 1C] Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Hindlimb grip strength was measured over time in female mice. Data are presented as mean ± standard error of mean (SEM) and analyzed by three-way analysis of variance or mixed-effects model. Each time point was analyzed using two-way analysis of variance, with Tukey's multiple comparison results shown as *p<0.05, **p<0.01, and ****p<0.0001. (The symbol "*" represents WT-Veh vs. HD-Veh, the symbol "$" represents WT-CORT113176 vs. HD-Veh, the symbol "+" represents WT-Veh vs. HD-CORT113176, and the symbol "Ω" represents WT-CORT113176 vs. HD-CORT113176.) [Figure 1D] Effect of HD genotype and CORT113176 treatment on functional parameters in mice. Total number of epileptic seizures in male and female mice. [Figure 1E]Effect of HD genotype and CORT113176 treatment on functional parameters in mice. Kaplan-Meier analysis of onset of epilepsy in male mice. [Figure 1F] Effect of HD genotype and CORT113176 treatment on functional parameters in mice. Kaplan-Meier analysis of the first onset of epilepsy in female mice. Epileptic seizures occurred most frequently in vehicle-treated female HD mice, but were never observed in CORT113176-treated female HD mice. [Figure 2A] Immunohistochemistry of markers associated with HD genotype in the striatum of male mice. Effects of HD genotype and CORT113176 on GFAP intensity in the male striatum. Data are shown as mean + standard error of mean (SEM) and analyzed using two-way ANOVA. Results of Tukey's multiple comparisons are shown as *p<0.05, **p<0.01, ***p<0.001. [Figure 2B] Immunohistochemistry of markers associated with HD genotype in the striatum of female mice. Effects of HD genotype and CORT113176 on GFAP intensity in the female striatum. Data are presented as mean + standard error of mean (SEM) and analyzed using two-way ANOVA. Results of Tukey's multiple comparisons are shown as *p<0.05, **p<0.01. [Figure 2C] Immunohistochemistry of markers associated with the HD genotype in the hippocampus of male mice. Effects of HD genotype and CORT113176 on GFAP intensity in the male hippocampus. Data are presented as mean + standard error of mean (SEM) and analyzed using two-way ANOVA. Tukey's multiple comparison results are indicated as *p<0.05. [Figure 2D] Immunohistochemistry of markers associated with HD genotype in the hippocampus of female mice. Effect of HD genotype and CORT113176 on GFAP intensity in the female hippocampus. Data are shown as mean + standard error (SEM). [Figure 2E]Immunohistochemistry of markers associated with HD genotype in the striatum and hippocampus of male mice. Effect of HD genotype and CORT113176 on Iba1 intensity in the male hippocampus. Data are shown as mean + standard error of mean (SEM). [Figure 3A] Effects of HD genotype and CORT113176 on mHtt aggregates in the striatum of male R6 / 2 mice. Average size of mHtt aggregates in the striatum of male R6 / 2 mice. Data are shown as mean + standard error of mean (SEM) and analyzed using one-way ANOVA. Tukey's multiple comparison results are indicated as *p<0.0001. [Figure 3B] Effect of HD genotype and CORT113176 on mHtt aggregates in the striatum of male R6 / 2 mice. Total mHtt area in the striatum of male R6 / 2 mice. Data are shown as mean + standard error of mean (SEM) and analyzed using one-way ANOVA. Tukey's multiple comparison results are shown as *p<0.05, **p<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0017] The methods disclosed herein can be used to treat patients suffering from Huntington's disease (HD) by administering an effective amount of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM that is effective to treat HD. In one embodiment, the heteroaryl ketone-fused azadecalin GRM is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (referred to as "dazcorilant" or "CORT113176") having the following structure:

[0018] [ka]

[0019] The GRM CORT113176 lacks significant cross-reactivity with other steroid receptors. In one embodiment, the octahydro-fused azadecalin GRM is the compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (zavacorilant, or referred to as "CORT125329") having the following structure:

[0020] [ka]

[0021] GRM Zavacorilant lacks significant cross-reactivity with other steroid receptors

[0022] Accordingly, applicants disclose herein a method for treating HD and its symptoms, comprising administering an effective amount of a GRM to a patient suffering from HD. In certain embodiments, the GRM is a heteroaryl ketone-fused azadecalin GRM, and in certain embodiments, the GRM is dazcorilant. Accordingly, disclosed herein are uses of heteroaryl ketone-fused azadecalin GRMs (e.g., including dazcorilant) for treating HD and its symptoms. Applicants also disclose herein the use of heteroaryl ketone-fused azadecalin GRMs (e.g., dazcorilant) in the manufacture of medicaments for treating HD and for treating the symptoms of HD.

[0023] The present applicant further discloses pharmaceutical compositions comprising a heteroaryl ketone-fused azadecalin GRM for treating HD. In some embodiments, the heteroaryl ketone-fused azadecalin GRM is dazcorilant. Such pharmaceutical compositions include, for example, capsules, tablets, pills, solutions, and emulsions comprising the heteroaryl ketone-fused azadecalin GRM (e.g., dazcorilant).

[0024] Accordingly, Applicants disclose herein that HD and symptoms of HD can be treated by administering an effective amount of a heteroaryl ketone-fused azadecalin GRM (e.g., dazcorilant). Symptoms of HD that can be treated by administering an effective amount of a heteroaryl ketone-fused azadecalin GRM (e.g., dazcorilant) include, but are not limited to, motor symptoms, neurological symptoms, and psychological symptoms.

[0025] As described above, Huntington's disease (HD) is a genetic neurodegenerative disorder caused by mutations in the huntingtin gene. Mutant huntingtin (mHtt) leads to cellular dysfunction, protein aggregation, and ultimately neuronal cell death. Patients with HD exhibit motor dysfunction, neurological symptoms and impairments, cognitive decline, and may have epileptic seizures. High levels of glucocorticoids have been found in HD patients and HD mouse models. Applicant herein discloses the results of a study evaluating the efficacy of the selective GRM CORT113176 in the commonly used R6 / 2 mouse model. This mouse model is characterized by severe motor dysfunction over the course of several weeks. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the onset of epileptic seizures. CORT113176 treatment also reduced clasping behavior and the onset of epileptic seizures in female mice. CORT113176 administration restored parameters altered in HD, including astrocyte markers in both the striatum and hippocampus and microglial markers in the hippocampus. CORT113176 delayed the formation of mHtt aggregates in the striatum and hippocampus. Applicants disclose herein results demonstrating that the heteroaryl ketone-fused azadecalin GRM CORT113176 can effectively delay several key symptoms associated with the HD phenotype in mice. Accordingly, Applicants disclose herein that heteroaryl ketone-fused azadecalin GRMs, such as CORT113176, administered to patients suffering from HD or symptoms of HD are effective treatments for HD and its symptoms.

[0026] definition Citations of scientific references are indicated by superscript numbers that refer to the list of references included at the end of this specification.

[0027] As used herein, the term "patient" refers to a human who is receiving, will be receiving, or has received medical care for a disease or condition.

[0028] As used herein, the terms "administer," "administering," "administered," or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. For example, the compound or composition can be administered orally to the patient.

[0029] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacological agent effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" can refer to the amount of a functional agent or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. An effective amount can be an amount effective to elicit a therapeutic response.

[0030] As used herein, the terms "administer," "administering," "administered," or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. Administration may be oral (i.e., the subject receives the compound or composition orally as a pill, capsule, liquid, or other form suitable for oral administration). Oral administration may be buccal (where the compound or composition is held in the mouth, e.g., under the tongue, and absorbed therein). Administration may be by injection, i.e., delivery of the compound or composition by needle, microneedle, pressurized syringe, or other means of piercing the skin or forcing the compound or composition through the subject's skin. Injection may be intravenous (i.e., injection into a vein); arterial (i.e., injection into an artery); intraperitoneal (i.e., injection into the peritoneum); intramuscular (i.e., injection into a muscle); or by other injection routes. Routes of administration may also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption through the skin from an implant containing the compound or composition), or by other routes.

[0031] As used herein, the term "combination therapy" refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents can be administered simultaneously or sequentially in any order during all or part of the treatment period. The at least two agents can be administered according to the same or different dosing regimens. In some cases, one agent is administered following a scheduled regimen, and the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, one pharmaceutical agent, e.g., an SGRM, is administered daily, and the other pharmaceutical agent, e.g., the other agent, is administered every two, three, or four days.

[0032] As used herein, the term "compound" is used to refer to a molecular moiety of a unique, identifiable chemical structure. A molecular moiety ("compound") can exist as a free species, where it is not associated with other molecules. A compound can also exist as part of a larger aggregate, where it is associated with other molecules, but nevertheless retains its chemical identity. A solvate, where a molecular moiety ("compound") of a defined chemical structure is associated with molecules of a solvent, is an example of such an associated form. A hydrate is a solvate where the associated solvent is water. A recitation of "compound" refers to the molecular moiety (of the recited structure) itself, whether it exists in free or associated form.

[0033] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0034] The term "glucocorticosteroid" ("GC") or "glucocorticoid" refers to a steroid hormone that binds to the glucocorticoid receptor. Glucocorticosteroids are typically characterized by 21 carbon atoms in ring A, an α,β-unsaturated ketone in ring A, and an α-ketol group attached to ring D, and vary in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19; see "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," edited by Daisy et al., Biochemistry, 1989, pg. 567.

[0035] As used herein, the term "glucocorticoid receptor" ("GR") refers to type II GR, a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs (e.g., dexamethasone) (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). Glucocorticoid receptors are also called cortisol receptors. This term includes GR, recombinant GR, and mutant GR isoforms.

[0036] The term "cortisol" refers to the naturally occurring glucocorticoid hormone (also known as hydrocortisone) produced by the zona fasciculata of the adrenal gland. Cortisol is the active glucocorticoid hormone in humans. Cortisol has the following structure:

[0037] [ka]

[0038] Cortisol can be measured from blood samples, saliva samples, urine samples, and other bodily fluid samples. Blood concentrations (e.g., serum cortisol levels) are thought to reflect short-term cortisol levels, while multiple blood samples from a single subject may show changes in cortisol levels measured over several hours. Urinary free cortisol (UFC) and salivary cortisol measurements are thought to reflect daily or longer-term cortisol levels and may therefore be useful for overall cortisol measurements summed over diurnal circadian variations. The term "total cortisol" refers to cortisol bound to cortisol-binding globulin (CBG or transcortin) in the blood and free cortisol (cortisol not bound to CBG). The term "free cortisol" refers to cortisol not bound to cortisol-binding globulin (CBG or transcortin) in the blood. As used herein, the term "cortisol" refers to total cortisol, free cortisol, and / or CBG-bound cortisol.

[0039] The term "corticosterone" refers to a natural glucocorticoid hormone produced in the adrenal gland that is active in rodents such as mice and rats. Corticosterone has the following structure:

[0040] [ka]

[0041] The term "normal level" refers to the average level of an analyte determined by measuring samples obtained from multiple normal subjects.

[0042] The terms "normal cortisol level" and "normal corticosterone level" refer to the average level of cortisol or corticosterone determined by measuring samples (e.g., serum samples) obtained from multiple normal subjects.

[0043] Blood levels of cortisol vary in humans during the day and at night. Normal morning cortisol levels (e.g., for a blood sample taken at approximately 8:00 AM) are about 5 micrograms per deciliter (mcg / dL) to about 25 mcg / dL (or about 138-140 nmol / L to about 690-700 nmol / L). Normal late afternoon cortisol levels (e.g., for a blood sample taken at approximately 4:00 PM) can range from about 3 mcg / dL to about 10 mcg / dL (or about 83-84 nmol / L to about 275-280 nmol / L). Normal values ​​are time-dependent and may depend on the laboratory and clinical setting in which the measurement is performed.

[0044] As used herein, a "blood sample" may be a whole blood sample, a serum sample, a plasma sample, or a blood cell sample suitable for measuring an analyte level by methods known in the art according to conventional usage. Similarly, the "blood level" of a particular analyte may be the level of the analyte in whole blood, serum, plasma, or blood cells. For example, the blood concentration of cortisol or corticosterone may be the level of that analyte in a serum or plasma sample taken from the subject being tested.

[0045] The term "average" refers to a value obtained by summing the values ​​obtained from a number of measurements and dividing by the number of measurements. The number of measurements can be any number greater than 1, although preferred numbers of measurements can be, for example, 3, 4, 5, 7, 10, 20, 25, 50, or more.

[0046] The term "about," when used in reference to a given value, indicates a range that encompasses ±10% of the given value.

[0047] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that regulates GC binding to GR or regulates any biological response associated with GR binding to an agonist.For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRM acting as an antagonist, such as mifepristone, reduces the activity of tyrosine aminotransferase (TAT) in HepG2 cells.TAT activity can be measured as described in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0048] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates GC binding to GR or modulates any biological response associated with the binding of GR to an agonist. By "selective," the drug preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). A selective glucocorticoid receptor modulator has a 10-fold higher affinity (K) for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d In a more preferred embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 100-fold greater (K ​​) than the affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d In other embodiments, the selective glucocorticoid receptor modulator binds to GR with an affinity (K 100-fold greater) than the affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. dCORT113176 and zavacorilant are SGRMs.

[0049] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits GC binding to GR or inhibits any biological response associated with GR binding to an agonist. Thus, GRMs can be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity can be measured as reviewed in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRAs are defined as compounds that inhibit the IC 50 (half-maximal inhibitory concentration) is less than 10 micromolar. See Example 1 of U.S. Patent No. 8,859,774.

[0050] As used herein, the term "selective glucocorticoid receptor antagonist" (SGRA) refers to any composition or compound that inhibits GC binding to GR or inhibits any biological response associated with GR binding to an agonist (inhibition is determined with respect to the response in the absence of the compound). By "selective," the drug preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). A selective glucocorticoid receptor antagonist has a 10-fold higher affinity (K) for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d In another preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 100-fold greater (K ​​) than its affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. dIn another preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 1000-fold greater (K ​​) than its affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d Preferably, they bind to GR with an affinity (1 / 1000th that of CORT113176 and zabacholant) are SGRAs.

[0051] As used herein, non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds containing a heteroaryl-ketone fused azadecalin structure (which may also be referred to as a heteroaryl-ketone fused azadecalin backbone) and compounds containing an octahydro-fused azadecalin structure (which may also be referred to as an octahydro-fused azadecalin backbone).

[0052] Exemplary nonsteroidal GRA, SGRA, GRM, and SGRM compounds containing a heteroaryl-ketone fused azadecalin structure include those described in U.S. Patent No. 8,859,774. Exemplary heteroaryl-ketone fused azadecalin GR modulator compounds (some of which may act as GRMs) are described in U.S. Patent Nos. 8,859,774, 9,273,047, 9,707,223, and 9,956,216, all of which are incorporated herein by reference in their entireties. Exemplary nonsteroidal GRA, SGRA, GRM, and SGRM compounds containing an octadolo-fused azadecalin structure include those described in U.S. Pat. No. 10,047,082, U.S. Pat. No. 10,323,034, U.S. Pat. No. 10,787,449, U.S. Pat. No. 11,370,789, and U.S. Pat. No. 11,560,379, all of which are incorporated herein by reference in their entireties.

[0053] Exemplary GRMs containing heteroaryl ketone-fused azadecalin structures include those described in U.S. Patent No. 8,859,774, which can be prepared as disclosed herein, and which is incorporated herein in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the GRM containing heteroaryl ketone-fused azadecalin structures has the following structure, or a salt or isomer thereof:

[0054] [ka]

[0055] During the ceremony, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R 1a and optionally substituted with 1 to 4 groups independently selected from R 1a are hydrogen and C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, N-oxide, C 3-8 Cycloalkyl, and C 3-8 independently selected from the group consisting of heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 2 are hydrogen and C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2aR 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R 2c optionally substituted with a group; Alternatively, two R attached to the same carbon 2 The groups combine to form an oxo group (=O); Or two R's 2 groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d optionally substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 2c are hydrogen, halogen, hydroxy, and C, respectively. 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, and -NR 2a R 2b independently selected from the group consisting of: R 2d are hydrogen and C, respectively. 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each contains 1 to 4 R 3a selected from the group consisting of phenyl and pyridyl, each optionally substituted by a group; R 3a are hydrogen, halogen, and C, respectively. 1-6independently selected from the group consisting of haloalkyl; The subscript n is an integer from 0 to 3.

[0056] In one embodiment, the GRM is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (referred to as "dazcorilant" or "CORT113176") having the following structure:

[0057] [ka]

[0058] Other GRMs containing a heteroaryl ketone-fused azadecalin structure suitable for use in the methods, uses, and compositions disclosed herein include, for example, the compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (designated "Relacorilant" or "CORT125134") having the following structure:

[0059] [ka]

[0060] Exemplary GRMs containing an octahydro-fused azadecalin structure include those described in U.S. Pat. No. 10,047,082, which can be prepared as disclosed herein, and which is incorporated herein in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the GRM containing an octahydro-fused azadecalin structure has the following structure, or a salt or isomer thereof:

[0061] [ka]

[0062] In the formula, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R 1a and R 1a are hydrogen and C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 2 are hydrogen and C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 cycloalkyl and C having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; 3-8 heterocycloalkyl; or two R on adjacent ring atoms are independently selected from the group consisting of: 2groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2c may be substituted with a group; R 2a , R 2b and R 2c are each independently hydrogen and C 1-6 alkyl; R 3a are each halogen; and the subscript n is an integer from 0 to 3.

[0063] In one embodiment, the octahydro-fused azadecalin nonsteroidal glucocorticoid receptor modulator is the compound having the following structure: ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (zavacorilant, or designated "CORT125329").

[0064] [ka]

[0065] Other GRMs containing an octahydro-fused azadecalin structure suitable for use in the methods, uses, and compositions disclosed herein include, for example, the compound having the following structure: ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (designated "exicholant" or "CORT125281").

[0066] [ka]

[0067] As used herein, the term "composition" is intended to encompass products containing specific components, such as the compounds, their tautomers, derivatives, analogs, stereoisomers, polymorphs, deuterated species, pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, pharmaceutically acceptable solvates, and specific amounts of pharmaceutically acceptable compositions, as well as any product resulting directly or indirectly from the combination of specific components in specific amounts. Such terms, with respect to pharmaceutical compositions, are intended to encompass products containing active ingredient(s) and inactive ingredient(s) comprising the carrier, as well as any product that directly or indirectly results in the combination, complexation, or aggregation of any two or more components, or the dissociation of one or more components, or any other type of reaction or interaction of one or more components. Thus, the pharmaceutical compositions of the present invention are intended to encompass any composition made by mixing the compounds of the present invention and their pharmaceutically acceptable carriers.

[0068] In some embodiments, the term "consisting essentially of" refers to a composition in which the active ingredient in the formulation is the only indicated active ingredient, but may also include other compounds that stabilize, preserve, etc. the formulation and are not directly involved in the therapeutic effect of the indicated active ingredient. In some embodiments, the term "consisting essentially of" can refer to a composition containing an active ingredient and ingredients that facilitate release of the active ingredient. For example, the composition can contain one or more ingredients that provide sustained release of the active ingredient over time to a subject. In some embodiments, the term "consisting essentially of" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0069] "Salt" refers to an acid or base salt of a compound used in the method of the present invention. Examples of pharmaceutically acceptable salts are mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0070] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration of—and absorption of—an active agent to—a subject and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidants, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds also can be incorporated into the compositions. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0071] Pharmaceutical Compositions and Administration In certain embodiments, the present invention provides a pharmaceutical composition for treating Huntington's disease (HD), the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an SGRM. In a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a non-steroidal SGRM having a heteroaryl-ketone-fused azadecalin structure or an octahydro-fused azadecalin structure.

[0072] GRMs and SGRMs (as used herein, GRMs and SGRMs include nonsteroidal GRMs and nonsteroidal SGRMS) can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. GRMs and SGRMs can also be administered by inhalation, e.g., intranasally. Additionally, GRMs and SGRMs can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a GRM or SGRM.

[0073] For preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details of techniques for formulation and administration are well described in the scientific and patent literature; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton PA ("Remington's").

[0074] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient, GRM, or SGRM. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0075] Powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier to provide a capsule, in which the active ingredient is surrounded by and thus associated with the carrier, with or without other carriers. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0076] Suitable solid excipients include, but are not limited to, sugars such as lactose, sucrose, mannitol, or sorbitol; starches derived from corn, wheat, rice, potato, or other plants; celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums including gum arabic and tragacanth; and proteins such as gelatin and collagen. If necessary, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0077] The dragee cores are provided with a suitable tablet coating, such as a concentrated sugar solution, which may contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). The pharmaceutical formulations of the present invention can also be administered orally using push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the GR modulator mixed with a filler or binder, such as lactose or starch, a lubricant, such as talc or magnesium stearate, and, optionally, a stabilizer. In soft capsules, the GR modulator compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0078] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0079] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a dispersant or wetting agent such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia, and naturally occurring phosphatides (e.g., lecithin), a viscous substance such as a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of an ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The preparations may be adjusted for osmotic pressure.

[0080] Also included are solid form preparations that are intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0081] Oil suspensions can be formulated by suspending the SGRM in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Oil suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners can be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These preparations can be preserved by the addition of an antioxidant such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be the above-mentioned vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as gum arabic and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents, as in the preparation of syrups and elixirs. Such preparations can also contain demulcents, preservatives, or coloring agents.

[0082] GRMs and SGRMs can be formulated transdermally, topically, as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0083] GRMs and SGRMs can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide constant delivery for weeks or months.

[0084] In some cases, the pharmaceutical formulations of the present invention can be provided as salts, which can be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the preparations may be lyophilized powders in the pH range of 4.5 to 5.5 in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, which are combined with a buffer prior to use.

[0085] In another embodiment, the formulations of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using a ligand bound to the liposome or directly bound to the oligonucleotide that binds to a cell surface membrane protein receptor that causes endocytosis. The use of liposomes can focus the delivery of GR modulators to target cells in vivo, especially if the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a specific organ. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0086] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient, GRM, or SGRM. The unit dosage form can be, for example, a package containing individual doses, such as packeted tablets, capsules, or powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0087] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, or from 1.0 mg to 6,000 mg, or from 5 mg to 5,000 mg, or from 10 mg to 2,000 mg, or from 15 mg to 1,500 mg, or from 20 mg to 1,250 mg, or from 25 mg to 1,000 mg, or from 50 mg to 750 mg. Suitable doses also include about 1 mg, 5, 10, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 150, 200, 225, 300, 375, 400, 450, 500, 550, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, depending on the particular application and potency of the active ingredient. The compositions may also contain other compatible therapeutic agents, as desired.

[0088] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the compound or composition of the present invention. The unit dosage form can be, for example, a packaged preparation containing individual doses, such as packeted tablets, capsules, or powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0089] The GRM can be administered orally. For example, the GRM can be administered as a pill, capsule, or liquid formulation as described herein. Alternatively, the GRM can be provided via parenteral administration. For example, the GRM can be administered intravenously (e.g., by injection or infusion). Additional methods of administering the compounds described herein and pharmaceutical compositions or formulations thereof are described herein.

[0090] In some embodiments, the GRM is administered in a single dose. In other embodiments, the GRM may be administered in multiple doses, such as two, three, four, five, six, seven, or more doses. In some cases, each dose may be the same amount. In other cases, each dose may be a different amount. The dose may increase or decrease gradually over the course of administration. The dose may vary depending, for example, on the nature of the GRM and the characteristics of the patient.

[0091] Any suitable GRM dose can be used in the methods disclosed herein. The dose of GRM administered can be at least about 10 milligrams per day (mg / day), or about 15 mg / day, or about 20 mg / day, or about 25 mg / day, or about 35 mg / day, or about 45 mg / day, or about 50 mg / day, or about 75 mg / day, or about 100 mg / day, or about 125 mg / day, or about 150 mg / day, or about 175 mg / day, or about 200 mg / day, or about 225 mg / day, or about 250 mg / day, or about 300 mg / day, or about 350 mg / day, or The GRM may be administered at about 375 mg / day, or about 400 mg / day, or about 450 mg / day, or about 500 mg / day, or about 525 mg / day, or about 550 mg / day, or about 600 mg / day, or about 675 mg / day, or about 700 mg / day, or about 750 mg / day, or about 800 mg / day, or about 825 mg / day, or about 900 mg / day, or about 975 mg / day, or about 1000 mg / day, or about 1050 mg / day, or about 1100 mg / day, or about 1200 mg / day, or more. In certain embodiments, the GRM is administered orally. In some embodiments, the GRM is administered in one or more doses. In other words, the GRM can be administered in one, two, three, four, five, six, seven, eight, nine, ten, or more doses. In certain embodiments, the GRM is orally administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times.

[0092] A subject may receive one or more doses of GRM, for example, over a 2-48 hour period, in one or more separate doses. In other embodiments, the GRM may be administered multiple times, for example, two, three, four, five, or more doses, over a 2-48 hour period. For example, the GRM may be administered over a period of 2, 3, 3, 4, 4, 5, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 28, 28, 30, 32, 34, 36, 40, 40, 42, 44, 46, or 48 hours. In some embodiments, the GRM may be administered over 2 to 48 hours, 2 to 36 hours, 2 to 24 hours, 2 to 12 hours, 2 to 8 hours, 8 to 12 hours, 8 to 24 hours, 8 to 36 hours, 8 to 48 hours, 9 to 36 hours, 9 to 24 hours, 9 to 20 hours, 9 to 12 hours, 12 to 48 hours, 12 to 36 hours, 12 to 24 hours, 18 to 48 hours, 18 to 36 hours, 18 to 24 hours, 24 to 36 hours, 24 to 48 hours, 36 to 48 hours, or 42 to 48 hours.

[0093] The formulations can be administered in single or multiple doses, depending on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the disease state. Thus, in one embodiment, a pharmaceutical formulation for oral administration of GRM is administered in a daily dose of about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In certain embodiments, the daily dose is about 0.1 to about 50 mg / kg / day, or about 0.5 to about 35 mg / kg / day, or about 1 to about 25 mg / kg / day, or about 2 to about 20 mg / kg / day. In certain embodiments, the daily dose of GRM is from about 10 milligrams per day (mg / day) to about 1200 mg / day, or from about 15 mg / day to about 1100 mg / day, or from about 20 mg / day to about 1000 mg / day, or from about 25 mg / day to about 975 mg / day, or from about 50 mg / day to about 900 mg / day, or from about 75 mg / day to about 825 mg / day, or from about 100 mg / day to about 800 mg / day, or from about 125 mg / day to about 750 mg / day, or from about 150 mg / day to about 500 mg / day.

[0094] In some embodiments, the GRM is orally administered to the patient. In some embodiments, the GRM is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks. In some embodiments, the GRM can be administered to the patient for longer than 80 weeks or even longer.

[0095] In some embodiments, administration of the GRM or SGRM is not continuous, but may be suspended for one or more periods, followed by one or more periods during which administration resumes, including weeks 5-9, 5-16, 9-16, 16-24, 16-32, 24-32, 24-48, 32-48, 32-52, 48-52, 48-64, 52-64, 52-72, 64-72, 64-80, 72-80, 72-88, 80-88, 80-96, 88-96, and 96-100. Suitable periods for which administration should cease also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, and 100 weeks.

[0096] Dosage regimens also take into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, bioavailability, metabolism, clearance, etc. (e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; the latest Remington's, supra). Current technology allows the clinician to determine the dosage regimen for each individual patient, GR modulator, and disease or condition being treated.

[0097] SGRMs can be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvants that are not effective alone but may contribute to the effectiveness of the active agent.

[0098] After a pharmaceutical composition containing a GRM or SGRM has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a GRM or SGRM, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0099] In another embodiment, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a cavity or lumen of an organ. Formulations for administration generally comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among acceptable vehicles and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable solutions. These solutions are sterile and generally free of undesirable matter. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the compositions of the present invention in these formulations can vary widely and is selected primarily based on fluid volume, viscosity, body weight, etc., in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the preparation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0100] I. Combination Therapy Administration of therapeutic compounds or agents to patients will follow conventional protocols for the administration of such compounds, taking into account the toxicity, if any, of the treatment. The method can be combined with other modalities of treatment.

[0101] Various combinations of a GRM or SGRM with another agent (or combination of such agent and compound) for treating Huntington's disease can be used to treat a patient. For example, tetrabenazine can be prescribed to a patient with HD; other drugs sometimes administered to patients with HD include haloperidol, risperidone, chlorpromazine, and amantadine. "Combination therapy" or "in combination with" does not mean that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein. The GRM or SGRM and the other agent can be administered according to the same or different dosing regimens. In some embodiments, the GRM or SGRM and the other agent are administered sequentially in any order for all or part of the treatment period. In some embodiments, the GRM or SGRM and the other agent are administered simultaneously or approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). Non-limiting examples of combination therapy are as follows, where administration of a GRM or SGRM and another therapeutic agent, eg, a GRM or SGRM, is "A" and the other therapeutic agent is "B."

[0102] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0103] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0104] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A [Example]

[0105] The following examples are offered by way of illustration only, and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.

[0106] Use of the glucocorticoid receptor modulator CORT113176 to treat motor and neuropathological symptoms of Huntington's disease in R6 / 2 mice Huntington's disease (HD) is an inherited neurodegenerative disorder caused by mutations in the huntingtin gene. Mutant huntingtin (mHtt) leads to cellular dysfunction, protein aggregation, and ultimately neuronal cell death. Patients with HD exhibit motor dysfunction and cognitive decline. High levels of glucocorticoids have been found in HD patients and in HD mouse models.

[0107] The glucocorticoid receptor modulators (GRMs) CORT113176 (also known as dazcorilant) and zabacorilant lack cross-reactivity with other steroid receptors. CORT113176 has been shown to be effective in treating Alzheimer's disease and amyotrophic lateral sclerosis (ALS). 7-10 .

[0108] We evaluated the efficacy of the selective GRM CORT113176 in alleviating HD symptoms in the commonly used R6 / 2 mouse model, which is characterized by severe motor decline over a period of several weeks. The results of this study showed that treatment with CORT113176 delayed the onset of some motor symptoms in male mice, but the effect was somewhat weaker in female HD mice. CORT113176 reduced the number of epileptic seizures observed in both mice (no seizures were observed in CORT113176-treated female mice). Region-specific changes in glial cells in HD mice were normalized by CORT113176 treatment. Furthermore, CORT113176 treatment reduced the formation of mHtt aggregates in the hippocampal CA1 and striatum.

[0109] Materials and methods used in this study animal HD and wild-type (WT) R6 / 2 mice were purchased from JAX (The Jackson Laboratory, ME, USA) and arrived at the animal facility at 4 weeks of age. Mice were housed under normal conditions (room temperature, 12-hour light / dark cycle) with free access to food and water. Mice were housed 3–4 per cage and separated by sex. However, to increase the survival rate of HD mice, mice of different genotypes were housed in the same cage. 11 Genotyping of tail samples collected postmortem was performed by Laragen (CA, USA) and confirmed that all HD mice had 120–130 CAG repeats.

[0110] Animal testing: experimental procedures Starting at 6 weeks of age, mice were injected subcutaneously (sc) daily with either 30 mg / kg CORT113176 or vehicle (Veh; 10% ethanol and castor oil in Experiment 1, or sesame oil in Experiment 2) for 5 consecutive weeks. In Experiment 1, male and female mice were assigned to one of the following groups: 1) WT+Veh (5 mice per sex), 2) WT+CORT113176 (n = 5), 3) HD+Veh (n = 5), or 4) HD+CORT113176 (n = 5). In the final analysis, due to mislabeling of genotypes and early endpoints in male mice, the number of individuals in each group was unequal: n = 6 for WT+Veh and n = 3 for HD+Veh. In Experiment 2, male mice were assigned to the following groups: 1) WT + Veh (n = 10), 2) HD + Veh (n = 10, but finally n = 8 due to non-responders who met outlier criteria and animals that reached the endpoint early), and 3) HD + CORT113176 (n = 10). Body weight was measured weekly, and motor function tests were performed at 1:00 PM to track disease progression (details described below). On days 19 and 34, blood samples were collected in the morning to assess corticosterone levels. On day 34, animals were sacrificed using CO2 inhalation, blood was collected by cardiac puncture, and the animals were perfused with cold PBS. Several tissues were then harvested and flash-frozen for further analysis. Brains were collected and stored in 4% PFA for 24 hours for IHC (details described below).

[0111] Motor function test Grip strength: Grip strength measurements were performed weekly to quantify muscle strength. For this procedure, mice were lifted by their tails in front of a rod attached to a Chatillon Grip Force Meter (Columbus Instruments, Ohio, USA) and forced to firmly grasp the grid with both forepaws. The mice were then gently pulled away until they lost their grip, and the force required to do so was monitored. This test was repeated 15 times with a short rest period after every 5 measurements. 12 The three highest scores were used for analysis.

[0112] Clasping test: The clasping test reveals that the corticostriatal pathway is a major input circuit of the basal ganglia, which controls many processes, including voluntary movement and motor coordination. 13 This procedure was performed weekly to assess the decline in the function of the hind limbs. For this procedure, mice were lifted by their tails to a height of approximately 50 cm for no more than 10 seconds. During this procedure, the hind limbs were observed and scored based on the position of the hind limbs relative to the abdomen, on a scale of 0 to 3. 14 This was repeated three times and the average score was used for analysis.

[0113] Epileptic seizures: Multiple (spontaneous) seizures were observed in HD mice during the study. These seizures were unexpected, but all cases were recorded throughout the experiment and assessed on the Racines scale. 15 was used to score.

[0114] immunohistochemistry Brains were isolated, and the left hemisphere was fixed in 4% PFA (Sigma-Aldrich, 8187085000) for 24 hours. The brains were then transferred to a 30% sucrose solution for 24-48 hours and stored at -80°C until further processing. 10 μM frozen sections were collected (CryoStar NX70) onto slides (Avantor, VWR® Microscope Slides, 631-1166) and stored at -20°C until staining. Slides were incubated with 0.1% Triton X-100 (Sigma-Aldrich) for 25 minutes and washed with 0.1% PBS / Tween (Tween® 20, Sigma-Aldrich). After blocking background signals with 5% PBSA for 30 min, slides were incubated overnight at 4°C with primary antibodies DARP32 (1:500, Abcam, EP720Y, ab40801), GFAP (1:500, Agilent DAKO, Z334), Iba1 (1:500, Fujifilm Wako, 019-19741), or mHtt (1:500, Abcam, EPR5526, ab209668). The next day, slides were washed with 0.1% PBS / Tween and then incubated with secondary antibody goat anti-rabbit Alexa Fluor 488 (1:250, Invitrogen, A-110088) for 30 min. After a final wash with 0.1% PBS / Tween, ProLong Gold containing DAPI (Invitrogen, P36931) was applied to the coverslip (Thermo-Fisher, Menzel-Glaser, 980), and the slides were allowed to dry at room temperature. DARP32, GFAP, and Iba1 slides were scanned using an Axio Slide Scanner (Zeiss, Axio Slide ScanZ1), and mHtt slides were analyzed using a confocal microscope (Leica, White Light Laser Confocal Microscope TCS SP8 X). All images were analyzed using ImageJ (version 1.52p). Mean intensities of DARP32, GFAP, and Iba1 were measured in the striatum and hippocampus.The total number of aggregates in a particular region of interest (ROI), the total area in the ROI, and the average size of the aggregates were determined.

[0115] Gene expression Frozen tissues were homogenized in Lysing Matrix D Minibead tubes (MP Biomedicals, #116913500) using TriPure isolation reagent (Roche, #11667165001), and total RNA was isolated according to the manufacturer's protocol. cDNA was synthesized using M-MLV reverse transcriptase (Promega, #M1705). Real-time quantitative PCR was performed using IQ SYBR-Green Supermix (Bio-Rad, #170-8885) and a Bio-Rad CFX96 system.

[0116] Example 1 Given the substantial differences between the sexes in response to CORT113176, data for male and female mice are shown separately.

[0117] CORT113176 treatment partially restores muscle strength in male but not female HD mice Forelimb grip strength was measured to assess the effect of CORT113176 on muscle function. Genotype effects were observed over time in both male and female mice. Muscle strength in male WT mice remained relatively stable over 5 weeks (Figure 1A). In contrast, vehicle-treated male HD mice showed a sustained decrease in grip strength beginning at week 2. CORT113176 treatment attenuated the decline in muscle function in these male HD mice. In Figures 1A, 1B, and 1C, filled circles represent results from vehicle-treated wild-type mice, open circles represent results from CORT113176-treated wild-type mice, filled triangles represent results from vehicle-treated HD mice, and open triangles represent results from CORT113176-treated HD mice.

[0118] CORT113176 treatment delays the increase in clasping scores in male and female HD mice A clasping test was performed to assess the effect of CORT113176 treatment on the impairment of the corticostriatal pathway, a critical pathway for locomotor activity and motor coordination. Higher clasping scores indicate a loss of voluntary motor coordination and therefore a more advanced HD phenotype. None of the WT mice exhibited clasping behavior. The authors observed genotype effects over time in both sexes.

[0119] In male mice, there was a significant interaction effect between HD and CORT113176. Vehicle-treated male HD mice showed increased clasping scores compared to WT mice starting at week 1 (Figure 1B), and CORT113176 treatment reduced clasping scores in HD mice compared to vehicle-treated HD mice.

[0120] In female mice, vehicle-treated HD mice showed increased clasping over time compared with WT mice (Figure 1C). There was an interaction between genotype, CORT113176 treatment, and time, suggesting that treatment prevented increases in clasping scores at later time points.

[0121] CORT113176 treatment prevents epileptic seizures in both sexes Epileptic seizures are a known symptom of juvenile HD (JHD), a pediatric form of Huntington's disease, and this feature is reproduced in the R6 / 2 mouse model. 25 All epileptic seizures observed during the experiment were recorded using the Racine scale. 15 The seizure was classified as a tonic-clonic seizure according to the classification method. Epileptic seizures occurred most frequently in vehicle-treated female HD mice but were never observed in CORT113176-treated female HD mice (Figure 1D). Overall, epileptic seizures occurred relatively infrequently in male HD mice, although the incidence of seizures was slightly higher in vehicle-treated HD mice compared with CORT113176-treated male HD mice (Figure 1D). Most epileptic seizures in CORT113176-treated HD mice occurred near the end of the 5-week period (day 32), whereas cases in vehicle-treated HD animals occurred throughout the entire 5-week study period (Figures 1E and 1F).

[0122] Astrocyte and microglial activity were assessed by GFAP and Iba1 staining, respectively. GFAP immunoreactivity in the striatum was significantly increased in both male and female HD mice compared with WT mice (Fig. 2A, HD: and 2B HD), and treatment with CORT113176 normalized GFAP levels in male mice but not in female mice (Fig. 2A, CORT113176: and Fig. 2B). A significant genotype effect was observed for Iba1 immunoreactivity in the striatum in both male and female mice.

[0123] Next, we evaluated astrocyte and microglial markers in the hippocampus. Within this brain region, a global trend across genotypes was observed for GFAP staining (Figure 2C, HD), with a significant decrease in GFAP staining intensity observed in vehicle-treated HD male mice compared to WT (Figure 2C). As with the striatum, CORT113176 treatment tended to normalize this HD effect (Figure 2C). A graphical representation of GFAP staining intensity in female mice is shown in Figure 2D. Iba1 intensity in male HD hippocampus tended to be higher with CORT113176 treatment (Figure 2E, CORT113176).

[0124] Example 2 The results disclosed in Example 1 demonstrate unexpected sex differences. We aimed to replicate and further evaluate the potential beneficial effects of CORT113176 treatment in a larger population of male R6 / 2 mice. The results confirmed the positive effects of CORT113176 administration on grip strength, grip behavior, and epileptic seizures.

[0125] CORT113176 treatment delays the onset of multiple motor symptoms in male HD mice Consistent with the above results, CORT113176 improved grip strength and reduced clasping scores compared to vehicle-treated mice. Only one epileptic seizure was observed in CORT113176-treated HD mice (at the end of the experiment), whereas vehicle-treated HD mice experienced multiple seizures earlier in the experimental period.

[0126] CORT113176 treatment reduces the formation of mutant huntingtin aggregates in the striatum and CA1 region of the hippocampus We evaluated the formation of mHtt aggregates, which are considered a hallmark of the HD phenotype. In the striatum, vehicle-treated HD mice showed a significant increase in the number of aggregates compared with WT mice. Treatment with CORT113176 significantly reduced the number of mHtt aggregates. The aggregates were similar in size in the vehicle- and CORT113176-treated HD groups (Figures 3A and 3B).

[0127] In the CA1 region of the hippocampus, the total number of aggregates was significantly increased in HD mice compared to WT mice. CORT113176-treated mice had significantly fewer aggregates in this brain region compared to vehicle-treated HD mice. In addition, CORT113176-treated mice had smaller aggregates and a smaller total aggregate area in the CA1 region compared to vehicle-treated HD mice.

[0128] Discussion and Summary In this study, we evaluated the efficacy of CORT113176, a selective GRM, in alleviating symptoms of HD in the R6 / 2 mouse model. Here, we show in two independent studies that CORT11376 delays several motor and neuropathological symptoms of HD in male mice.

[0129] In mice, treatment with CORT113176 was observed to alleviate some HD-related symptoms. Thus, treatment with CORT113176 partially improved grip strength and significantly reduced clasping scores. Furthermore, CORT113176 treatment significantly improved the performance of JHD and R6 / 2 models. 16-17 CORT113176 prevented the onset of epileptic seizures commonly seen in male R6 / 2 mice. CORT113176 also reduced protein aggregation in the brains of male R6 / 2 mice (female mice were not evaluated). Taken together, there was clear efficacy of CORT113176 in the CNS, particularly in male mice.

[0130] All patents, patent publications, publications, and patent applications cited herein are incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Additionally, although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of the present invention, certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0131] Reference materials 1. Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OF, Sousa N, et al. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration. Neural Plast. 2016;2016:6391686. 2. Schakman O, Kalista S, Barbe C, Loumaye A, Thissen JP. Glucocorticoid-induced skeletal muscle atrophy. Int J Biochem Cell Biol. 2013;45(10):2163-72. 3. Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol. 2007;275(1-2):43-61. 4. Bjorkqvist M, Petersen A, Bacos K, Isaacs J, Norlen P, Gil J, et al. Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6 / 2 transgenic mouse model of Huntington's disease. Hum Mol Genet. 2006;15(10):1713-21. 5. Dufour BD, McBride JL. Corticosterone dysregulation exacerbates disease progression in the R6 / 2 transgenic mouse model of Huntington's disease. Exp Neurol. 2016;283(Pt A):308-17. 6. Morton AJ, Lagan MA, Skepper JN, Dunnett SB. Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation. J Neurocytol. 2000;29(9):679-702. 7. Hunt HJ, Belanoff JK, Golding E, Gourdet B, Phillips T, Swift D, et al. 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GRMs with reduced hERG inhibition and an improved pharmacokinetic profile. Bioorg Med Chem Lett. 2015;25(24):5720-5. 8. Pineau F, Canet G, Desrumaux C, Hunt H, Chevallier N, Ollivier M, et al. New selective glucocorticoid receptor modulators reverse amyloid-beta peptide-induced hippocampus toxicity. Neurobiol Aging. 2016;45:109-22. 9. Meyer M, Lara A, Hunt H, Belanoff J, de Kloet ER, Gonzalez Deniselle MC, et al. The Selective Glucocorticoid Receptor Modulator Cort 113176 Reduces Neurodegeneration and Neuroinflammation in Wobbler Mice Spinal Cord. Neuroscience. 2018;384:384-96. 10. Meyer M, Kruse MS, Garay L, Lima A, Roig P, Hunt H, et al. Long-term effects of the glucocorticoid receptor modulator CORT113176 in murine motoneuron degeneration. Brain Res. 2020;1727. 11. Story D, Gallien J, Al-Gharaibeh A, Sandstrom M, Rossignol J, Dunbar GL. Housing R6 / 2 Mice with Wild-Type Littermates Increases Lifespan. J Huntingtons Dis. 2021;10(4):455-8. 12. Aartsma-Rus A, van Putten M. Assessing functional performance in the mdx mouse model. J Vis Exp. 2014(85). 13. Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci. 2016;18(1):7-21. 14. Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, Garden GA. A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp. 2010(39). 15. Van Erum J, Van Dam D, De Deyn PP. PTZ-induced seizures in mice require a revised Racine scale. Epilepsy Behav. 2019;95:51-5. 16. Thakor B, Jagtap SA, Joshi A. Juvenile Huntington's disease masquerading as progressive myoclonus epilepsy. Epilepsy Behav Rep. 2021;16:100470.

[0132] 17. Cepeda C, Oikonomou KD, Cummings D, Barry J, Yazon VW, Chen DT, et al. Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations. J Neurosci Res. 2019;97(12):1624-35.

Claims

1. A method for treating a patient suffering from Huntington's disease (HD), comprising administering to the patient an effective amount of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM that is effective in treating HD.

2. 2. The method of claim 1, wherein the GRM is a heteroaryl ketone-fused azadecalin GRM.

3. 2. The method of claim 1, wherein the GRM is an octahydrofused azadecalin GRM.

4. 10. The method of claim 1, wherein the treatment is effective to treat the symptoms of HD.

5. 5. The method of claim 4, wherein the symptom of HD is a motor symptom of HD.

6. 5. The method of claim 4, wherein the symptom of HD is a neurological or psychological symptom of HD.

7. the motor symptoms of HD are selected from the group consisting of involuntary, jerky, jerky movements (convulsions), involuntary, writhing movements (chorea); muscle contractions or rigidity (dystonia); tremors; slowed or abnormal eye movements; muscle weakness; decreased grasp; gait disturbance (i.e., difficulty walking); balance disturbance; swallowing disturbance; breathing disturbance; abnormal posture; decreased ability to stand upright; decreased ability to maintain head position; and speech disturbance; The impairment is determined by comparing the ability to perform motor activities with a baseline (e.g., before the onset of HD symptoms or at the time of initial diagnosis of HD symptoms), 6. The method of claim 5, wherein administration of said effective amount of said heteroaryl ketone-fused azadecalin GRM or said octahydro-fused azadecalin GRM is effective in treating motor symptoms of HD.

8. 7. The method of claim 6, wherein the symptoms of HD include epileptic seizures and the treatment is effective in reducing the frequency of the epileptic seizures.

9. 7. The method of claim 6, wherein the symptoms of HD include epileptic seizures and the treatment is effective in reducing the frequency or severity of the epileptic seizures.

10. the symptom of HD is a neurological or psychological symptom selected from the group of neurological symptoms consisting of amnesia; other memory loss; confusion; speech disorder; poor concentration; slow comprehension; delirium; hallucinations; paranoia; depression; anxiety; apathy; and rapid or sudden mood swings; Impairment is determined by comparison with a baseline level of ability or neurological or psychological activity or symptoms (e.g., before the onset of HD symptoms or at the time of initial diagnosis of HD symptoms), 7. The method of claim 6, wherein said administration of an effective amount of said heteroaryl ketone-fused azadecalin GRM or said octahydro-fused azadecalin GRM is effective to treat said neurological or psychological symptoms of HD.

11. The method of any one of claims 1 to 10, wherein the GRM is a heteroaryl ketone-fused azadecalin GRM, and the GRM has the chemical structure of the following formula: or a salt or isomer thereof: 【Chemistry 1】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, CN, N-oxide, C ３－８ Cycloalkyl, and C ３－８ independently selected from the group consisting of heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ Cycloalkyl, and C ３－８ heterocycloalkyl, wherein said heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R ２ｃ optionally substituted with a group; Alternatively, two R groups attached to the same carbon atom ２ groups combine to form an oxo group (=O); Or, two R ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｄ optionally substituted with a group; R ２ａ and R ２ｂ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ２ｃ are hydrogen, halogen, hydroxy, and C １－６ Alkoxy, C １－６ Haloalkoxy, CN, and NR ２ａ R ２ｂ are independently selected from the group consisting of: R ２ｄ are hydrogen and C １－６ alkyl, or two R attached to the same ring atom ２ｄ the groups combine to form (=O); R ３ Each of these has 1 to 4 R ３ａ selected from the group consisting of phenyl and pyridyl, each optionally substituted by a group; R ３ａ are hydrogen, halogen, and C, respectively. １－６ independently selected from the group consisting of haloalkyl; The subscript n is an integer from 0 to 3.

12. 12. The method of claim 11 , wherein the heteroaryl ketone-fused azadecalin GRM is dazcorilant ((R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone), having the following structure: 【Chemistry 2】

13. 11. The method of any one of claims 1 to 10, wherein the GRM is an octahydrofused azadecalin GRM, and the GRM has the chemical structure of the following formula: or a salt or isomer thereof: 【Transformation 3】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, N-oxide, and C ３－８ cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ cycloalkyl and C having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; ３－８ independently selected from the group consisting of heterocycloalkyl; Alternatively, two R on adjacent ring atoms ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｃ optionally substituted with a group; R ２ａ , R ２ｂ and R ２ｃ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ３ａ are each halogen; and the subscript n is an integer from 0 to 3.

14. 14. The method of claim 13, wherein the octahydro-fused azadecalin GRM is zavacholant ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone), having the following structure: 【Chemistry 4】

15. 1. A pharmaceutical composition for treating Huntington's disease (HD) or a symptom thereof, comprising a pharmaceutically acceptable excipient and a non-steroidal glucocorticoid receptor modulator (GRM) compound comprising a heteroaryl ketone-fused azadecalin structure of the following formula, or a salt or isomer thereof: 【Transformation 5】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, CN, N-oxide, C ３－８ Cycloalkyl, and C ３－８ independently selected from the group consisting of heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ Cycloalkyl, and C ３－８ heterocycloalkyl, wherein said heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R ２ｃ optionally substituted with a group; Alternatively, two R groups attached to the same carbon atom ２ groups combine to form an oxo group (=O); Or, two R ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｄ optionally substituted with a group; R ２ａ and R ２ｂ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ２ｃ are hydrogen, halogen, hydroxy, and C １－６ Alkoxy, C １－６ Haloalkoxy, CN, and NR ２ａ R ２ｂ are independently selected from the group consisting of: R ２ｄ are hydrogen and C １－６ alkyl, or two R attached to the same ring atom ２ｄ the groups combine to form (=O); R ３ Each of these has 1 to 4 R ３ａ selected from the group consisting of phenyl and pyridyl, each optionally substituted by a group; R ３ａ are hydrogen, halogen, and C, respectively. １－６ independently selected from the group consisting of haloalkyl; The subscript n is an integer from 0 to 3.

16. 16. The pharmaceutical composition of claim 15, wherein the non-steroidal GRM compound containing a heteroaryl ketone-fused azadecalin structure is dazcorilant ((R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone), having the following structure: 【Transformation 6】

17. 1. A pharmaceutical composition for treating Huntington's disease (HD) or a symptom thereof, comprising a pharmaceutically acceptable excipient and a non-steroidal glucocorticoid receptor modulator (GRM) compound comprising an octahydro-fused azadecalin structure of the following formula, or a salt or isomer thereof: 【Transformation 7】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, N-oxide, and C ３－８ cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ cycloalkyl and C having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; ３－８ independently selected from the group consisting of heterocycloalkyl; Alternatively, two R on adjacent ring atoms ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｃ optionally substituted with a group; R ２ａ , R ２ｂ and R ２ｃ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ３ａ are each halogen; and the subscript n is an integer from 0 to 3.

18. 18. The pharmaceutical composition of claim 17, wherein the non-steroidal GRM compound comprising an octahydro-fused azadecalin structure is zavacorilant ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone), having the following structure: 【Transformation 8】

19. 16. The pharmaceutical composition for treating the symptoms of HD according to claim 15, wherein the symptoms of HD are motor function symptoms of HD.

20. 16. The pharmaceutical composition for treating the symptoms of HD according to claim 15, wherein the symptoms of HD are neurological or psychological symptoms of HD.

21. 18. The pharmaceutical composition for treating the symptoms of HD according to claim 17, wherein the symptoms of HD are motor function symptoms of HD.

22. 18. The pharmaceutical composition for treating the symptoms of HD according to claim 17, wherein the symptoms of HD are neurological or psychological symptoms of HD.

23. Use of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM for treating Huntington's disease (HD) or a symptom thereof.

24. Use of a heteroaryl ketone-fused azadecalin GRM or an octahydro-fused azadecalin GRM in the manufacture of a medicament for treating Huntington's disease (HD) or a symptom thereof.

25. 25. The use of claim 23 or claim 24, wherein the treatment of HD comprises treating the symptoms of HD.

26. The use according to any one of claims 23 to 25, wherein the treatment of HD comprises treating elevated cortisol levels in patients with HD.

27. The use according to any one of claims 23 to 25, wherein the treatment of HD comprises treating motor symptoms of HD.

28. 26. The use according to any one of claims 23 to 25, wherein said treating HD comprises treating neurological or psychological symptoms of HD.

29. 26. The use of any one of claims 23 to 25, wherein the treatment of HD comprises treating a motor symptom of HD selected from the group consisting of involuntary, sudden, jerking movements (convulsions), involuntary, writhing movements (chorea); muscle contractions or rigidity (dystonia); tremors; slowed or abnormal eye movements; muscle weakness; poor grip; gait disturbances (i.e., difficulty walking); balance disorders; swallowing disorders; breathing disorders; abnormal posture; decreased ability to stand upright; decreased ability to maintain head position; and speech disorders.

30. 26. The use according to any one of claims 23 to 25, wherein the treatment of HD comprises the treatment of epileptic seizures.

31. 26. The use of any one of claims 23 to 25, wherein the treatment of HD comprises treating a neurological or psychological symptom of HD selected from the group consisting of amnesia; other memory loss; confusion; speech disturbance; poor concentration; slowed comprehension; delirium; hallucinations; paranoia; depression; anxiety; apathy; and rapid or sudden mood swings.

32. The use of any one of claims 23 to 31, wherein the GRM is a heteroaryl ketone-fused azadecalin GRM comprising the chemical structure of the following formula, or a salt or isomer thereof: 【Chemistry 9】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, CN, N-oxide, C ３－８ Cycloalkyl, and C ３－８ independently selected from the group consisting of heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ Cycloalkyl, and C ３－８ heterocycloalkyl, wherein said heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R ２ｃ optionally substituted with a group; Alternatively, two R groups attached to the same carbon atom ２ groups combine to form an oxo group (=O); Or, two R ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｄ optionally substituted with a group; R ２ａ and R ２ｂ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ２ｃ are hydrogen, halogen, hydroxy, and C １－６ Alkoxy, C １－６ Haloalkoxy, CN, and NR ２ａ R ２ｂ are independently selected from the group consisting of: R ２ｄ are hydrogen and C １－６ alkyl, or two R attached to the same ring atom ２ｄ the groups combine to form (=O); R ３ Each of these has 1 to 4 R ３ａ selected from the group consisting of phenyl and pyridyl, each optionally substituted by a group; R ３ａ are hydrogen, halogen, and C, respectively. １－６ independently selected from the group consisting of haloalkyl; The subscript n is an integer from 0 to 3.

33. 33. The use of claim 32, wherein the heteroaryl ketone-fused azadecalin GRM is dazcorilant ((R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone), having the following structure: 【Chemistry 10】

34. The use of any one of claims 23 to 31, wherein the GRM is an octahydrofused azadecalin GRM comprising the chemical structure of the following formula, or a salt or isomer thereof: 【Chemistry 11】 During the ceremony, R １ is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R １ａ and optionally substituted with 1 to 4 groups independently selected from R １ａ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, N-oxide, and C ３－８ cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R ２ are hydrogen and C, respectively. １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl-C １－６ Alkoxy, CN, OH, NR ２ａ R ２ｂ , C(O)R ２ａ , C(O)OR ２ａ , C(O)NR ２ａ R ２ｂ , S.R. ２ａ , S(O)R ２ａ , S(O) ２ R ２ａ , C ３－８ cycloalkyl and C having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; ３－８ independently selected from the group consisting of heterocycloalkyl; Alternatively, two R on adjacent ring atoms ２ The groups combine to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is ２ｃ optionally substituted with a group; R ２ａ , R ２ｂ and R ２ｃ are each independently hydrogen and C １－６ selected from the group consisting of alkyl; R ３ａ are each halogen; and the subscript n is an integer from 0 to 3.

35. 35. The use of claim 34, wherein the non-steroidal GRM compound comprising an octahydro-fused azadecalin GRM is zavacorilant ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone), having the following structure: 【Chemistry 12】

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