Methods and compositions for treating huntington's disease and symptoms thereof

Abstract

Methods and compositions for treating a patient suffering from Huntington's disease or treating symptoms thereof are disclosed. The methods comprise administering to the patient an effective amount of a heteroaryl ketone fused aza-naphthane glucocorticoid receptor modulator (GRM) or an octahydro fused aza-naphthane GRM. In an embodiment, the GRM is Dargencolan. In some embodiments, the GRM is zaltile blue. In embodiments, the GRM is administered orally. In some embodiments, the GRM is administered daily; in other embodiments, the GRM is administered in a regimen, such as once every day, once every three days, once per week, or other administration regimen. The symptoms of Huntington's disease that can be treated by the methods described herein include, but are not limited to, motor symptoms (e.g., muscle weakness, posture abnormalities, walking difficulty, dysphagia) and neurological or psychological symptoms (e.g., seizure, amnesia, consciousness disorder, impaired verbal ability, delirium, depression, anxiety).

Description

Background Art

[0001] Huntington's disease (HD), also known as Huntington's chorea, is a hereditary neurodegenerative disorder characterized by impaired motor function and cognitive decline, psychiatric impairment, muscle atrophy, and metabolic dysfunction. According to the World Federation of Neurology, chorea is characterized by excessive, spontaneous movements that are irregular, non-repetitive, randomly distributed, and occur suddenly. These movements are referred to as "choreiform" movements.

[0002] HD is caused by an excessive number of CAG repeats (35+) in the Huntington's gene. This increase in CAG repeats results in a mutant huntingtin protein (mHtt), which acquires toxic functions and partially loses its native function. This mutant protein, mHtt, promotes pathological interactions and aggregates in the brain, leading to cellular dysfunction and ultimately neuronal death. mHtt aggregates are the neuropathological hallmark of the disease. Patients with HD experience a progressive deterioration in cognitive, motor, and metabolic function. HD is a terminal disease, with death typically occurring approximately 15 to 30 years after the initial onset of symptoms.

[0003] Currently, treatment for HD is primarily symptomatic and limited to helping patients cope with the disease itself and the psychological issues that coexist with a progressive, end-stage neurological disease. Tetrabenazine may be prescribed to try to reduce the frequency or severity of sudden or abnormal choreiform limb movements associated with HD. Although not yet approved for such use, medications such as haloperidol, risperidone, chlorpromazine, and amantadine may also be used to try to reduce the frequency or severity of these unwanted choreiform movements associated with HD. Antidepressant or antianxiety medications may be prescribed to try to alleviate the depression or anxiety experienced by many people with HD. High levels of endogenous glucocorticoids are associated with a variety of HD-related symptoms, including neurodegeneration, cognitive decline, muscle atrophy, and metabolic dysfunction. 1-3 The R6 / 2 mouse strain is the most commonly used HD model, showing elevated glucocorticoid levels, mHtt aggregates, and various motor symptoms. 4-6 .

[0004] The glucocorticoids Cortisol (e.g., humans) and corticosterone (e.g., rodents) are steroid hormones produced by the adrenal glands that act throughout the body. Cortisol and corticosterone exert their effects by binding to the glucocorticoid receptor (GR). The most commonly used GR modulator (GRM), mifepristone (RU486), is not specific for the GR; it also has affinity for other nuclear steroid receptors, such as the progesterone receptor (PR) and the androgen receptor (AR). This lack of selectivity for the GR may result in side effects related to PR or AR activity when used for the GR, or may result in side effects related to GR activity when used for, for example, the PR or AR.

[0005] Therefore, there is a need in the art for more effective treatments for HD. As such treatments are relevant to human cortisol activity, there is a need for GRMs that are more selective for the cortisol receptor (GR) than mifepristone. Summary of the Invention

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

[0007] Motor symptoms may include, but are not limited to, for example, involuntary jerking movements (spasticity); involuntary writhing movements (chorea); muscle contractions or stiffness (dystonia); tremor; slowed or abnormal eye movements; impaired muscle strength; impaired grip; impaired gait (i.e., difficulty walking); impaired balance; impaired swallowing; impaired respiratory function; impaired posture; impaired uprightness; impaired ability to maintain head position; impaired speech; and other motor symptoms, where impairment is determined by comparison to the ability to perform motor activities at baseline (e.g., before the onset of HD symptoms or at the time of initial diagnosis of HD symptoms).

[0008] Neurological and psychological symptoms may include, but are not limited to, for example, seizures; amnesia; other memory loss; confusion; impaired speech; impaired attention; impaired speed of comprehension; delirium; hallucinations; paranoia; depression; anxiety; apathy; rapid or unexplained changes in mood; and other neurological or psychological symptoms, where impairment is determined by comparison to a baseline capacity 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 an embodiment, the GRM is a selective GRM (SGRM) that is active at the GR but has little or no activity at other steroid hormone receptors (e.g., minimal or no activity at the PR or AR). In an embodiment, the GRM is a nonsteroidal compound comprising a heteroaryl-keto-fused azadecalin structure, wherein the heteroaryl-keto-fused azadecalin structure is as described and disclosed in U.S. Patent No. 8,859,774. In an embodiment, the GRM is a nonsteroidal compound comprising an octahydro-fused azadecalin structure, wherein the octahydro-fused azadecalin structure is as described and disclosed in U.S. Patent No. 10,047,082.

[0010] In an embodiment, the GRM is a compound comprising a heteroaryl ketone-fused azadecalin structure (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (known as "dazucorilant" or "CORT113176") having the following structure:

[0011] In an embodiment, the GRM is a compound comprising an octahydrofused azadecalin 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 (known as "zavacorilant" or "CORT125329") having the following structure: US Patent 8,859,774 and US Patent 10,047,082 are incorporated herein by reference in their entirety.

[0012] In an embodiment, the GRM is administered orally to the patient. GRM treatment for treating HD or HD symptoms may include daily GRM administration (e.g., once a day, twice a day, or other daily administration regimens); or may include intermittent GRM administration (e.g., once every other day, once every three days, twice a week, or other administration regimens). In an embodiment, the effective amount of the GRM is from about 1 to about 100 milligrams per kilogram (mg / kg). For example, the GRM dosage for daily GRM administration for treating HD or treating HD symptoms is from about 1 to about 100 milligrams per kilogram per day (mg / kg / day), or from about 3 mg / kg / day to about 75 mg / kg / day, or from about 5 mg / kg / day to about 50 mg / kg / day. In embodiments, the daily dose of the GRM is from about 5 milligrams / day (mg / day) to about 3000 mg / day, or from about 10 mg / day to about 2500 mg / day, or from about 20 mg / day to about 2250 mg / day, or from about 30 mg / day to about 2000 mg / day, or from about 40 mg / day to about 1750 mg / day, or from about 50 mg / day to about 1500 mg / day, or from about 75 mg / day to about 1000 mg / day, or from about 100 mg / day to about 750 mg / day, or from about 150 mg / day to about 500 mg / day. GRM treatment can be administered continuously as needed; thus, such treatment can be continued for a year, or for several years, or for many years. In embodiments, GRM treatment comprises administration of the GRM for at least 1 week to about 80 weeks, or longer. The GRM can be administered concurrently with other medications or treatments currently being taken by the HD patient, or can be administered while the HD patient is receiving other medications or treatments for HD or its symptoms.

[0013] The methods described herein provide improved methods for treating HD and HD symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] 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 ± SEM and analyzed using a three-way ANOVA or mixed-effects model. Data were analyzed using a two-way ANOVA at each time point with Tukey's multiple comparisons. *p < 0.05, + = WT-Veh vs. HD-CORT113176.

[0015] Figure 1BEffects of HD genotype and CORT113176 treatment on functional parameters in mice. Hindlimb grasp scores were measured over time in male mice. Data are presented as mean ± SEM and analyzed using a three-way ANOVA or mixed-effects model. Data were analyzed using a two-way ANOVA for each time point and were compared with Tukey's multiple comparisons. ***p < 0.001, ****p < 0.0001 (* = WT-Veh vs. HD-Veh, $ = WT-CORT113176 vs. HD-Veh, # = HD-CORT113176 vs. HD-Veh).

[0016] Figure 1C Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Hindlimb grasp scores were measured over time in female mice. Data are presented as mean ± SEM and analyzed using a three-way ANOVA or mixed-effects model. Individual time points were analyzed using a two-way ANOVA with Tukey's multiple comparisons. *p < 0.05, **p < 0.01, ****p < 0.0001 (* = WT-Veh vs. HD-Veh, $ = WT-CORT113176 vs. HD-Veh, + = WT-Veh vs. HD-CORT113176, and Ω = WT-CORT113176 vs. HD-CORT113176).

[0017] Figure 1D Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Total number of seizures in male and female mice.

[0018] Figure 1E Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Kaplan-Meier analysis of first-epilepsy episodes in male mice.

[0019] Figure 1F Effects of HD genotype and CORT113176 treatment on functional parameters in mice. Kaplan-Meier analysis of the first seizure in female mice. Seizures occurred most frequently in vehicle-treated female HD mice, whereas no seizures were observed in CORT113176-treated female HD mice.

[0020] Figure 2AImmunohistochemistry for markers associated with HD genotype in the striatum of male mice. Effects of HD genotype and CORT113176 on GFAP intensity in the striatum of male mice. Data are presented as mean ± SEM and analyzed by two-way ANOVA with Tukey's multiple comparisons. *p < 0.05, **p < 0.01, and ***p < 0.001.

[0021] Figure 2B Immunohistochemistry for markers associated with HD genotype in the striatum of female mice. Effects of HD genotype and CORT113176 on GFAP intensity in the striatum of female mice. Data are presented as mean ± SEM and analyzed by two-way ANOVA with Tukey's multiple comparisons. *p < 0.05 and **p < 0.01 are presented.

[0022] Figure 2C Immunohistochemistry for markers associated with HD genotype in the hippocampus of male mice. Effects of HD genotype and CORT113176 on GFAP intensity in the hippocampus of male mice. Data are presented as mean ± SEM and analyzed by two-way ANOVA. *p < 0.05 is indicated by Tukey's multiple comparisons.

[0023] Figure 2D Immunohistochemistry for markers associated with HD genotype in the hippocampus of female mice. Effects of HD genotype and CORT113176 on GFAP intensity in the hippocampus of female mice. Data are presented as mean ± SEM.

[0024] Figure 2E Immunohistochemistry for markers associated with HD genotype in the striatum and hippocampus of male mice. Effects of HD genotype and CORT113176 on Iba1 intensity in the hippocampus of male mice. Data are presented as mean ± SEM.

[0025] Figure 3A Effects of HD genotype and CORT113176 on mHtt aggregates in the striatum of male R6 / 2 mice. Average mHtt aggregate size in the striatum of male R6 / 2 mice. Data are presented as mean ± SEM and analyzed by one-way ANOVA with Tukey's multiple comparisons. ****p<0.0001.

[0026] Figure 3BEffects 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 presented as mean ± SEM and analyzed by one-way ANOVA with Tukey's multiple comparisons. *p < 0.05 and **p < 0.01. DETAILED DESCRIPTION

[0027] Disclosed herein is a method for treating a patient suffering from Huntington's disease (HD), comprising administering an effective amount of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM to effectively treat HD. In an 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-pyrazolo[P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (known as "dazucolan" or "CORT113176"), which has the following structure: The GRM CORT113176 lacks significant cross-reactivity with other steroid receptors. In an embodiment, the octahydrofused 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 (known as "zavakolan" or "CORT125329"), which has the following structure: GRM zavakolan lacks significant cross-reactivity with other steroid receptors.

[0028] Thus, applicants disclose herein methods for treating HD and its symptoms, comprising administering an effective amount of a GRM to a patient suffering from HD. In some embodiments, the GRM is a heteroaryl ketone-fused azadecalin GRM; in specific embodiments, the GRM is darzucoline. Thus, disclosed herein are the uses of heteroaryl ketone-fused azadecalin GRMs (including, for example, darzucoline) for treating HD and its symptoms. Applicants also disclose herein the use of heteroaryl ketone-fused azadecalin GRMs (e.g., darzucoline) in the manufacture of a medicament for treating HD and its symptoms.

[0029] Applicants further disclose pharmaceutical compositions comprising heteroaryl ketone-fused azadecalin GRMs for use in treating HD. In embodiments, the heteroaryl ketone-fused azadecalin GRM is darzucolan. Such pharmaceutical compositions include, for example, capsules, tablets, pills, solutions, and emulsions comprising heteroaryl ketone-fused azadecalin GRMs (e.g., darzucolan).

[0030] Thus, applicants disclose herein that HD and its symptoms can be treated by administering an effective amount of a heteroaryl ketone-fused azadecalin GRM, such as dazucalin. HD symptoms that can be treated by administering an effective amount of a heteroaryl ketone-fused azadecalin GRM, such as dazucalin, include, but are not limited to, motor symptoms, neurological symptoms, and psychological symptoms.

[0031] As mentioned above, Huntington's disease (HD) is an inherited neurodegenerative disease caused by mutations in the Huntington gene. Mutant huntingtin protein (mHtt) causes cell dysfunction, protein aggregation, and ultimately neuronal cell death. Patients with HD exhibit impaired motor function, neurological symptoms and impairment, cognitive decline, and may experience epileptic seizures. Elevated glucocorticoid levels are present in HD patients and HD mouse models. Applicants disclose herein 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 decline within a few weeks. In male mice, CORT113176 treatment significantly delayed the decline in grip strength, the occurrence of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment also reduced clasping behavior and epileptic seizures in female mice. CORT113176 administration restored parameters altered in HD, including astrocyte markers in the striatum and hippocampus, and microglial markers in the hippocampus. CORT113176 delayed the formation of mHtt aggregates in the striatum and hippocampus. The results disclosed herein by the applicants indicate that the heteroaryl ketone-fused azadecalin GRM CORT113176 can effectively delay several key symptoms associated with the HD phenotype in mice. Therefore, the applicants disclose herein that administering a heteroaryl ketone-fused azadecalin GRM (such as CORT113176) to patients suffering from HD or experiencing HD symptoms is an effective method for treating HD and its symptoms. definition

[0032] Citations to scientific references are indicated by superscript numbers which refer to the list of references given at the end of this specification.

[0033] As used herein, the term "patient" refers to a person who is receiving, will receive, or has received medical care for a disease or condition.

[0034] As used herein, the terms "administering," "administering," "administered," or "administered" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. For example, a compound or composition can be administered orally to a patient.

[0035] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmaceutical agent that is effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to an amount of a functional agent or pharmaceutical composition that can be used to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any test method known in the art. An effective amount can be an amount effective to elicit a therapeutic response.

[0036] As used herein, the terms "administer / give", "administer", "administered" or "administered" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. Administration can be by oral administration (i.e., the subject receives the compound or composition by oral administration in the form of a pill, capsule, liquid or other suitable for oral administration). Oral administration can be buccal (wherein the compound or composition is contained in the oral cavity, e.g., sublingually, and absorbed therein). Administration can be by injection, i.e., by a needle, microneedle, pressure syringe or other method of piercing the skin or forcing the compound or composition through the subject's skin. Injection can be intravenous (i.e., into a vein), intraarterial (i.e., into an artery), intraperitoneal (i.e., into the peritoneum), intramuscular (i.e., into a muscle) or by other injection routes. Administration routes can also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition) or by other routes.

[0037] As used herein, the term "combination / combination therapy" refers to administering at least two agents to a subject to treat a disease. The two agents can be administered simultaneously or sequentially in any order throughout the treatment period or a portion of the treatment period. At least two agents can be administered according to the same or different dosing schedules. In some cases, one agent is administered according to a predetermined schedule and the other agent is administered intermittently. In some cases, two agents are administered intermittently. In some embodiments, one agent (e.g., SGRM) is administered daily, while the other agent (e.g., other agent) is administered every two, three, or four days.

[0038] As used herein, the term "compound" is used to refer to a molecular moiety with a unique, identifiable chemical structure. A molecular moiety ("compound") can exist in a free form, in which it is not associated with other molecules. A compound can also exist as part of a larger aggregate, in which it is associated with one or more other molecules, but still retains its chemical identity. A solvate is an example of such an associated form, in which a molecular moiety with a defined chemical structure ("compound") is associated with solvent molecules. A hydrate is a solvate in which the associated solvent is water. Reference to a "compound" refers to the molecular moiety (having the recited structure) itself, whether in a free or associated form.

[0039] 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. Unless any conventional media or agents are incompatible with the active compound, their use in the composition is contemplated. Supplementary active compounds may also be incorporated into the composition.

[0040] The term "glucocorticoid" ("GC") or "glucocorticoid" refers to a steroid hormone that is bound to the glucocorticoid receptor. Glucocorticoids are generally characterized in that they have 21 carbon atoms, an α in ring A, a β-unsaturated ketone, an α-keto alcohol group connected to ring D. They differ in the degree of oxidation and hydroxylation of C-11, C-17, and C-19 (Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," Biochemistry, Daisy et al. (eds.), 1989, p. 567).

[0041] As used herein, the term "glucocorticoid receptor (GR)" refers to type II GR, which is an intracellular receptor that specifically binds to Cortisol and / or Cortisol analogs such as dexamethasone (see, e.g., Turner and Muller, J. Mol. Endocrinol. 2005 Oct 1 35:283-292). The glucocorticoid receptor is also known as the Cortisol receptor. The term includes isomers of GR, recombinant GR, and mutant GR.

[0042] The term "cortisol" refers to a naturally occurring glucocorticoid (also known as hydrocortisone) produced by the zona fasciculata of the adrenal glands. Cortisol is the active glucocorticoid in the human body. Cortisol has the following structure: Cortisol can be measured by blood sample, saliva sample, urine sample and other body fluid samples.Blood level (for example, serum cortisol level) is considered to reflect short-term cortisol level, and multiple blood samples from single object can show the change of the cortisol level measured in a few hours.Urine free cortisol (UFC) and saliva cortisol measurement value are considered to reflect daily or long-term cortisol level, therefore may contribute to summarizing the overall cortisol measurement value of circadian rhythm change in one day.Term " total cortisol " refers to the cortisol and free cortisol (cortisol not bound to CBG) that are bound to cortisol binding globulin (CBG or cortisol transfer protein) in blood.Term " free cortisol " refers to the cortisol that is not bound to cortisol binding globulin (CBG or cortisol transfer protein) in blood.As used herein, term " cortisol " refers to total cortisol, free cortisol and / or the cortisol combined with CBG.

[0043] The term "corticosterone" refers to a naturally occurring glucocorticoid produced by the adrenal glands that is active in rodents such as mice and rats. Corticosterone has the following structure:

[0044] The term "normal level" refers to the average level of an analyte determined by measuring samples obtained from a plurality of normal subjects.

[0045] The terms "normal Cortisol levels" and "normal corticosterone levels" refer to average levels of Cortisol or corticosterone determined by measuring samples (eg, serum samples) obtained from a plurality of normal subjects.

[0046] Cortisol levels in a person's blood vary during the day and at night. A normal morning cortisol level (e.g., a blood sample collected around 8 a.m.) is about 5 micrograms per deciliter (mcg / dL) to about 25 mcg / dL (or about 138-140 nmol / L to about 690-700 nmol / L). A normal evening cortisol level (e.g., a blood sample collected around 4 p.m.) may be about 3 mcg / dL to about 10 mcg / dL (or about 83-84 nmol / L to about 275-280 nmol / L). Normal values ​​depend on the time of day and may also depend on the laboratory and clinical setting in which the measurement is made.

[0047] As used herein, a "blood sample" can be a whole blood sample, serum sample, plasma sample, or blood cell sample suitable for measuring the level of an analyte according to conventional applications by methods known in the art. Similarly, a "blood level" of a particular analyte can be the level of the analyte in whole blood, serum, plasma, or blood cells. For example, the blood level of cortisol or corticosterone can be the level of the analyte in a serum or plasma sample taken from a subject.

[0048] The term "average value" refers to the value obtained by adding the values ​​obtained from multiple measurements and dividing it by the number of measurements. The number of measurements can be any number greater than 1; however, the preferred number of measurements can be, for example, 3, 4, 5, 7, 10, 20, 25, 50 or more.

[0049] When applied to a predetermined value, the term "about" is intended to encompass a range of ±10% of the predetermined value.

[0050] The term "glucocorticoid receptor modulator (GRM)" refers to any compound that regulates the binding of GC to GR or regulates any biological reaction associated with the binding of GR to an agonist. For example, GRMs as agonists (such as dexamethasone) can increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRMs as antagonists (such as mifepristone) can reduce the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as described in the literature: A.Ali et al., J.Med.Chem., 2004, 47, 2441-2452.

[0051] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates the binding of GC to GR, or modulates any biological response associated with the binding of GR to an agonist. By "selective," the drug preferentially binds to the GR over other nuclear receptors, such as the progesterone receptor (PR), the mineralocorticoid receptor (MR), or the androgen receptor (AR). Preferably, the selective glucocorticoid receptor modulator binds to the GR with an affinity that is 10 times greater than its affinity for the binding of the 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 affinity of the selective glucocorticoid receptor modulator for binding to GR is 100 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR. d In another embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR. d CORT113176 and Zawakolan are SGRMs.

[0052] A "glucocorticoid receptor antagonist" (GRA) is any compound that inhibits the binding of GC to GR, or any biological reaction associated with the binding of GR 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 described in: A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRA is an IC 50 Compounds with a (half maximal inhibitory concentration) of less than 10 micromolar. See Example 1 of U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference.

[0053] 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 (wherein the inhibition is determined relative to the response in the absence of the compound). By "selective," the drug preferentially binds to the GR rather than other nuclear receptors, such as the progesterone receptor (PR), the mineralocorticoid receptor (MR), or the androgen receptor (AR). Preferably, the selective glucocorticoid receptor antagonist binds to the GR with an affinity that is 10 times greater than its affinity for binding to the MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR (K < 0.05). d In a more preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 100 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR. d In another embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 1000 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR. d CORT113176 and Zawakolan are SGRA.

[0054] As used herein, nonsteroidal 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).

[0055] Exemplary nonsteroidal GRA, SGRA, GRM, and SGRM compounds containing a heteroaryl ketone-fused azadecalin structure include those described in U.S. Pat. No. 8,859,774. Exemplary heteroaryl ketone-fused azadecalin GR modulator compounds (some of which can function as GRMs) are described in U.S. Pat. No. 8,859,774; U.S. Pat. No. 9,273,047; U.S. Pat. No. 9,707,223; and U.S. Pat. No. 9,956,216, all of which are hereby incorporated by reference in their entireties. Exemplary nonsteroidal GRA, SGRA, GRM, and SGRM compounds containing an octahydrofused 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 hereby incorporated by reference in their entireties.

[0056] Exemplary GRMs comprising heteroaryl ketone-fused azadecalin structures include those described in U.S. Patent No. 8,859,774, which can be prepared as disclosed in that patent, which is incorporated herein by reference in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the GRM comprising heteroaryl ketone-fused azadecalin structures has the following structure: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from: hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, N-oxide, C 3-8 Cycloalkyl and C 3-8 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 atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from: hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C1-6 Alkoxy, -CN, -OH, -NR 2a R 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 is optionally substituted by 1 to 4 R 2c group substitution; Alternatively, two R attached to the same carbon 2 The 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 atoms and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted by 1 to 3 R 2d group substitution; R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 2c Independently selected from the following groups: hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN and -NR 2a R 2b ; Each R 2d independently selected from the group consisting of hydrogen and C 1-6 Alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1 to 4 R 3a group substitution; Each R 3a Independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and Subscript n is an integer from 0 to 3; or its salts and isomers.

[0057] In an embodiment, the GRM is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (known as "dazucolan" or "CORT113176"), which has the following structure:

[0058] Other GRMs containing heteroaryl ketone-fused azadecalin structures 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 (also known as "relaquerine" or "CORT125134"), which has the following structure:

[0059] Exemplary GRMs comprising an octahydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082, which can be prepared as disclosed therein, which is incorporated herein by reference in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the GRM comprising an octahydro-fused azadecalin structure has the following structure: where R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms, optionally substituted by 1 to 4 members each independently selected from R 1a The heteroatoms are independently selected from the following groups: N, O and S; each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, 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, each having 5 to 6 ring atoms and 1 to 4 heteroatoms, each independently selected from the group consisting of N, O, and S; each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R2b 、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 having 1 to 3 heteroatoms 3-8 Heterocycloalkyl, wherein the heteroatoms are each independently selected from the following group: N, O and S; or, two R on adjacent ring atoms 2 The groups combine to form a heterocycloalkyl ring having 5 to 6 ring atoms and 1 to 3 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1 to 3 R 2c Group substitution; R 2a 、R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 Alkyl; each R 3a are independently halogen; and subscript n is an integer from 0 to 3, or salts and isomers thereof.

[0060] In an embodiment, the octahydro-fused azadecalin nonsteroidal glucocorticoid receptor modulator 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 (known as "zavakolan" or "CORT125329"), which has the following structure:

[0061] Other GRMs containing an octahydro-fused azadecalin structure suitable for use in the methods, uses, and compositions disclosed herein include, for example, the compound ((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 (also known as "Ixicolan" or "CORT125281"), which has the following structure:

[0062] As used herein, the term "composition" is intended to encompass products comprising specified ingredients, such as the compound, its tautomeric forms, its derivatives, its analogs, its stereoisomers, its polymorphs, its deuterated species, its pharmaceutically acceptable salts, esters, ethers, metabolites, isomer mixtures, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable compositions thereof in specified amounts, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. For pharmaceutical compositions, the term is intended to encompass products comprising the active ingredients and inert ingredients constituting a vehicle, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or the decomposition of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present invention are intended to encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable vehicle thereof.

[0063] In some embodiments, the term "consisting essentially of" refers to a composition in which the only active ingredient in the formulation is the stated active ingredient, but may also include other compounds that are used to stabilize, preserve the formulation, etc., but are not directly related to the therapeutic effect of the stated active ingredient. In some embodiments, the term "consisting essentially of" may refer to a composition comprising an active ingredient and a component that promotes the release of the active ingredient. For example, the composition may include one or more components that provide for the sustained release of the active ingredient to a subject over time. In some embodiments, the term "consisting of" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0064] "Salt" refers to an acid or base salt of a compound used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts include: inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0065] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration of an active agent to a subject and its absorption by the subject, and can 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 agents, and absorption delaying agents that are compatible with drug administration. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings, and pigments. It will be understood by those of ordinary skill in the art that other pharmaceutical excipients can be used in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active compound, their use in the composition should be considered. Supplementary active compounds may also be incorporated into the composition. It will be appreciated by those of ordinary skill in the art that other pharmaceutically acceptable excipients may be used in the present invention. Pharmaceutical compositions and administration

[0066] In one embodiment, the present invention provides a pharmaceutical composition for treating Huntington's disease (HD), 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.

[0067] GRMs and SGRMs (as used herein, GRMs and SGRMs include non-steroidal GRMs and non-steroidal SGRMs) can be prepared and administered in a variety of oral, parenteral and topical dosage forms. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for patient intake. GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. Similarly, GRMs and SGRMs can be administered by inhalation (e.g., intranasal inhalation). In addition, GRMs and SGRMs can be administered transdermally. Therefore, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a GRM or SGRM.

[0068] For preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material. Details about formulations and administration techniques are widely described in the scientific and patent literature, for example, in the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co. ("Remington") in Easton, Pennsylvania.

[0069] In powders, the carrier is a finely divided solid which is mixed 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 into the desired shape and size.

[0070] The powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are 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 "formulation" is intended to include formulations of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and thereby associated with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0071] Suitable solid excipients are carbohydrate or protein fillers, including but not limited to: sugars, including lactose, sucrose, mannitol or sorbitan; starch from corn, wheat, rice, potato or other plants; cellulose, such as methylcellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose; gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen. If necessary, a disintegrant or solubilizer, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, may be added.

[0072] The dragee core is coated with a suitable coating agent, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or dragee coating for product labeling or to characterize the amount of active compound (i.e., dosage). The pharmaceutical formulations of the present invention can also be administered orally in the form of push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a coating agent 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 a fatty oil, liquid paraffin, or liquid polyethylene glycol, with or without a stabilizer.

[0073] Liquid form 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.

[0074] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavorings, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with a viscous material, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; a dispersing or wetting agent, for example, a naturally occurring phosphatide (for example, lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain fatty alcohol (for example, heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester of a fatty acid and a hexitol (for example, polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide with a partial ester of a fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension 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 formulation may be osmotically adjusted.

[0075] Also included are solid form preparations that are converted into liquid form preparations for oral administration before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, the preparation may also contain coloring agents, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0076] Oily suspensions can be prepared 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. The oily suspension may contain a thickener such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners such as glycerol, sorbitol, or sucrose may be added to provide a palatable oral formulation. These formulations may be preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oily carrier, see Minto, J.Pharmacol.Exp.Ther.281:93-102,1997. The pharmaceutical preparations of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or mineral oil as described above, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and gum tragacanth, naturally occurring phospholipids such as soy lecithin, esters or partial esters of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings, as in the case of syrups and elixirs. Such preparations may also contain a demulcent, a preservative, or a coloring agent.

[0077] GRMs and SGRMs can be delivered transdermally by topical routes and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, spreads, powders, and aerosols.

[0078] GRM and SGRM can also be delivered in the form of microspheres for sustained release in vivo. For example, microspheres can be administered by intradermal injection of microspheres containing the drug, which are slowly released 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 stable, sustained delivery over several weeks or months.

[0079] In some cases, the pharmaceutical formulations of the present invention may be provided in salt form and can be formed using a variety 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 formulations may be provided as a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, and combined with a buffer prior to use.

[0080] In another embodiment, the formulations of the present invention can be delivered by using liposomes that fuse with or are endocytosed by the cell membrane, i.e., by using a ligand attached to the liposome (or directly attached to the oligonucleotide) that binds to the cell's surface membrane protein receptor, leading to endocytosis. By using liposomes, especially when the liposomes carry a ligand specific for the target cell on their surface, or otherwise preferentially target a specific organ, the delivery of the GR modulator can be concentrated to the target cell in vivo. (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).

[0081] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient GRM or SGRM. The unit dosage form can be a kit containing discrete, metered doses, such as pre-packed tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form can itself be a capsule, tablet, cachet, or lozenge, or a suitable amount of any of these in a kit.

[0082] The quantity of active ingredient in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, or 1.0 mg to 6000 mg, or 5 mg to 5000 mg, or 10 mg to 2000 mg, or 15 mg to 1500 mg, or 20 mg to 1250 mg, or 25 mg to 1000 mg, or 50 mg to 750 mg. Depending on the specific application and the potency of the active ingredient, suitable dosages 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. If desired, the composition may also contain other compatible therapeutic agents.

[0083] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a kit comprising discrete, metered doses, such as pre-packed tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form can itself be a capsule, tablet, cachet, or lozenge, or a suitable quantity of any of these dosage forms in a kit.

[0084] 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 by parenteral administration. For example, the GRM can be administered intravenously (e.g., by injection or infusion). Other methods of administering the compounds described herein, their pharmaceutical compositions, or their formulations are described herein.

[0085] In some embodiments, the GRM is administered in a single dose. In other embodiments, the GRM is administered in more than one dose, such as two, three, four, five, six, seven, or more doses. In some cases, the doses are equal. In other cases, the doses are unequal. The dose may be increased or gradually decreased during administration. The amount will vary depending on, for example, the properties of the GRM and the patient's characteristics.

[0086] Any suitable GRM dosage can be used in the methods disclosed herein. The GRM dosage administered can be at least about 10 milligrams (mg) 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 about 450 mg / day. In some embodiments, the GRM is administered orally. In some embodiments, the GRM is administered orally at least one dose. In other words, the GRM can be administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In embodiments, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0087] In some embodiments, the GRM is administered in one dose. In other embodiments, the GRM is administered in more than one dose, such as 2, 3, 4, 5 or more doses, over a 2-48 hour period, such as a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 14 hour period, a 16 hour period, a 18 hour period, a 20 hour period, a 22 hour period, a 24 hour period, a 26 hour period, a 28 hour period, a 30 hour period, a 32 hour period, a 34 hour period, a 36 hour period, a 38 hour period, a 40 hour period, a 42 hour period, a 44 hour period, a 46 hour period, or a 48 hour period. In some embodiments, the GRM is administered over a period of 2-48 hours, 2-36 hours, 2-24 hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48 hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36 hours, 24-48 hours, 36-48 hours, or 42-48 hours.

[0088] Single or multiple formulations can be administered according to the dosage and frequency required and tolerated by the patient. The formulation should provide enough active agent to effectively treat the disease state. Therefore, in one embodiment, the daily dose of the pharmaceutical formulation for oral administration of GRM is about 0.01 mg to about 150 mg per kilogram of body weight per day (mg / kg / day). In some 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 embodiments, the daily dose of the GRM is from about 10 milligrams / day (mg / day) to about 1,200 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.

[0089] In an embodiment, the GRM is administered orally to a patient. In an embodiment, 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 an embodiment, the GRM is administered for more than 80 weeks, or even longer.

[0090] In some embodiments, GRM or SGRM administration is not continuous, and one or more time courses can be suspended, and then one or more time courses are resumed. The suitable time courses wherein suspension is administered include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-100 weeks. Among the suitable times for discontinuation are 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.

[0091] The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., absorption rate, bioavailability, metabolism, clearance, etc. (see, 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; and Remington, supra). The current art allows the clinician to determine the dosage regimen for each patient, GR modulator, and disease or condition being treated.

[0092] SGRMs may be used in combination with other agents known to be useful in modulating the glucocorticoid receptor, or with adjunctive agents that may not be effective alone but may aid in the efficacy of the agent.

[0093] After the pharmaceutical composition comprising the GRM or SGRM has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for use in treating the indicated condition. For administration of the GRM or SGRM, such labeling should include, for example, instructions for the amount, frequency, and method of administration.

[0094] In another embodiment, the compositions of the present invention can be used for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or organ cavity. The formulation for administration will generally comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents include water and Ringer's solution (isotonic sodium chloride). In addition, sterile, non-volatile oils are generally used as solvents or suspending media. To this end, various low-irritation non-volatile oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. These solutions are sterile and generally free of unwanted substances. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances required to simulate physiological conditions, such as pH adjusters and buffers, and toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these formulations can be adjusted over a wide range, primarily depending on the selected mode of administration and the patient's needs, based on fluid volume, viscosity, body weight, etc. For intravenous administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. Suspensions can be prepared according to known methods using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions dissolved in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. I. Combination / Combination Therapy

[0095] Administration of the therapeutic compound or agent to the patient will follow general protocols for administration of such compounds, taking into account the toxicity of the treatment (if necessary).The present method can be used in conjunction with other therapeutic modalities.

[0096] Various combinations of a GRM or SGRM with another agent for treating Huntington's disease (or a combination of such agents and compounds) can be used to treat a patient. For example, tetrabenazine can be prescribed to a patient with HD; other drugs sometimes given to HD patients include, for example, haloperidol, risperidone, chlorpromazine, and amantadine. By "combination / combination therapy" or "combination / combination use" it is not meant that the therapeutic agents must be administered at the same time 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 schedules. In some embodiments, the GRM or SGRM and the other agent are administered sequentially in any order throughout the treatment period or a portion 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, taking the administration of a GRM or SGRM and another therapeutic agent as an example, the GRM or SGRM is "A" and the other therapeutic agent is "B":

[0097] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0098] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0099] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A. Example

[0100] The following examples are provided for illustration only and are not intended to be limiting. A person skilled in the art will readily appreciate that a number of non-critical parameters may be varied or modified while yielding substantially the same or similar results. Treatment of motor and neuropathological symptoms of Huntington's disease in R6 / 2 mice using the glucocorticoid receptor modulator CORT113176

[0101] 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. HD patients exhibit impaired motor function and cognitive decline. Elevated glucocorticoid levels are observed in HD patients and HD mouse models.

[0102] The glucocorticoid receptor modulators (GRMs) CORT113176 (also known as dazukolan) and zavackolan lack cross-reactivity with other steroid receptors. CORT113176 has been shown to be effective in models of Alzheimer's disease and amyotrophic lateral sclerosis (ALS). 7-10 .

[0103] We evaluated the efficacy of the selective GRM CORT113176 in alleviating symptoms in the commonly used R6 / 2 mouse model of HD, characterized by severe motor decline over several weeks. These findings demonstrate that CORT113176 treatment delays multiple motor symptoms in male, but less so in female, HD mice. CORT113176 reduced the number of seizures observed in both sexes (no seizures were observed in CORT113176-treated female mice). CORT113176 treatment normalized region-specific changes in glial cells in HD mice. Finally, CORT113176 treatment reduced the formation of mHtt aggregates in the CA1 region of the hippocampus and striatum. Materials and methods used in this study animal

[0104] HD and wild-type (WT) R6 / 2 mice were purchased from JAX (The Jackson Laboratory, Maine, USA) and delivered to the animal facility at 4 weeks of age. Mice were housed under normal conditions (room temperature, 12-h light / dark cycle) with free access to food and water. Three to four mice were housed per cage, separated by sex, but mice of different genotypes were housed together to improve the survival rate of HD mice. 11 Tail samples collected post-mortem were genotyped by Laragen (California, USA) to confirm that all HD mice had 120-130 CAG repeats.

[0105] Animal studies: experimental proceduresStarting at 6 weeks of age, mice were injected subcutaneously (sc) daily for five consecutive weeks with 30 mg / kg CORT113176 or vehicle (Veh; 10% ethanol and castor oil in Experiment 1 or sesame oil in Experiment 2). In Experiment 1, male and female mice were assigned to one of the following groups: 1) WT + Veh (n = 5 per sex), 2) WT + CORT113176 (n = 5), 3) HD + Veh (n = 5), or 4) HD + CORT113176 (n = 5). In the final analysis, male mice were unevenly distributed due to genotype mislabeling and mice reaching the endpoint prematurely, i.e., n = 6 in the WT + Veh group and n = 3 in the HD + Veh group. In Experiment 2, male mice were assigned to the following groups: WT+Veh (n=10); HD+Veh (n=10, final n=8 due to non-responders meeting outlier criteria and mice reaching the time point early); HD+CORT113176 (n=10). Body weight was measured weekly and exercise testing was performed at 1 pm to monitor disease progression (as 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 ice-cold PBS. Afterwards, some tissues were harvested and snap-frozen for further analysis. Brains were collected and stored in 4% PFA for 24 hours for IHC (as described below). Motor function research

[0106] Grip strength: Grip strength was measured weekly to quantify muscle strength. The measurement method was as follows: the mouse was lifted by its tail and placed in front of a metal bar connected to a Chatillon dynamometer (Columbus Instruments, Ohio, USA) and asked to grasp the metal bar with both forepaws. The mouse was then gently pulled away until the grip was lost, and the force required was measured. This test was repeated 15 times with a short rest between every 5 measurements. 12 The three highest scores were used for analysis.

[0107] Grip test: A weekly grip test is performed to assess the degree of degeneration of the cortico-striatal pathway, which is the main input circuit of the basal ganglia and controls multiple processes including voluntary movement and motor coordination. 13 During this procedure, the mouse is lifted by the tail to a height of approximately 50 cm for a duration of no more than 10 seconds. During this procedure, the mouse's hind limbs are observed and scored 0-3 points based on their position relative to the abdomen. 14 The experiment was repeated three times and the average value was used for analysis.

[0108] epileptic seizuresDuring the study, multiple (spontaneous) seizures were observed in HD mice. These seizures were not expected, but each seizure was recorded throughout the experiment and scored using the Racine scale. 15 .

[0109] Immunohistochemistry The brain was isolated and the left hemisphere was fixed with 4% PFA (Sigma-Aldrich, 8187085000) for 24 hours. Afterwards, the brain was transferred to a 30% sucrose solution for 24-48 hours and stored at -80°C until further processing. 10 μM cryosections (CryoStar NX70) were collected on slides (Avantor, The slides were incubated with 0.1% TritonX-100 (Sigma-Aldrich) for 25 minutes and then washed with 0.1% PBS / Tween ( 20, Sigma-Aldrich). Background signals were blocked with 5% PBSA for 30 minutes, followed by incubation with primary antibodies against DARP32 (1:500, abcam, EP720Y, ab40801), GFAP (1:500, Agilent DAKO, Z0334), Iba1 (1:500, Fujifilm Wako Pure Chemical Industries, Ltd., 019-19741), or mHtt (1:500, abcam, EPR5526, ab209668) at 4°C overnight. The following day, slides were washed with 0.1% PBS / Tween and incubated with secondary antibodies against goat anti-rabbit AlexaFluor 488 (1:250, Invitrogen, A-110088) for 30 minutes. After washing with 0.1% PBS / Tween, ProLong gold (Invitrogen, P36931) containing DAPI was added to the coverslip (Thermo-Fisher, Menzel- 0980) and the slides were dried at room temperature. Slides for DARP32, GFAP, and Iba1 were scanned using an Axio slide scanner (Zeiss, Axio Slide Scan.Z1), and mHtt slides were analyzed using a confocal microscope (Leica, white light laser confocal microscope TCS SP8 X). All acquired images were analyzed using ImageJ (version 1.52p). The average intensity of DARP32, GFAP, and Iba1 in the striatum and hippocampus was measured. The total number of aggregates within a specific region of interest (ROI), the total area within the ROI, and the average size of the aggregates were measured.

[0110] Gene expression Frozen tissue was placed in Lysing Matrix D Minibead tubes (MP Biomedicals, product number 116913500) and homogenized using TriPure isolation reagent (Roche, product number 11667165001), and total RNA was isolated according to the manufacturer's protocol. cDNA was synthesized using M-MLV reverse transcriptase (Promega, product number M1705). Real-time quantitative PCR was performed using IQ SYBR-Green Supermix (Bio-Rad, product number 170-8885) and a Bio-Rad CFX96 system. Example 1

[0111] Given the significant sex differences in response to CORT113176, data for male and female mice are presented separately. CORT113176 treatment partially restores muscle strength in male HD mice but not in female HD mice

[0112] Forelimb grip strength was measured to assess the effect of CORT113176 on muscle function. We observed genotype effects over time in both male and female mice. Muscle strength in male wild-type mice remained relatively stable over five weeks (Figure 1.A). In contrast, grip strength in male HD mice treated with vehicle steadily decreased over time, starting at week 2. CORT113176 treatment attenuated this decline in muscle function in male HD mice. Figure 1A 、 1B In 1C and 1C, solid circles represent the results of wild-type mice treated with vehicle; open circles represent the results of wild-type mice treated with CORT113176; solid triangles represent the results of HD mice treated with vehicle; and open triangles represent the results of HD mice treated with CORT113176. CORT113176 treatment delays clasping scores in male and female HD mice

[0113] A grasping test was performed to assess the effect of CORT113176 treatment on the decreased function of the cortico-striatal pathway, which is important for voluntary movement and motor coordination. Higher grasping scores indicate a loss of voluntary motor coordination and, therefore, a more pronounced progression of the HD phenotype. None of the wild-type mice exhibited grasping behavior. We observed a genotype effect that varied over time in both sexes.

[0114] In male mice, a significant interaction was observed between HD and CORT113176. Compared with wild-type mice, vehicle-treated male HD mice showed increased clasping scores starting from week 1 ( Figure 1B ), while CORT113176-treated HD mice had reduced clasping scores compared to vehicle-treated HD mice.

[0115] In female mice, vehicle-treated HD mice showed increased clasping ability over time compared to wild-type mice ( Figure 1C There was an interaction between genotype, CORT113176 treatment, and time, indicating that treatment did reduce clasping scores at later time points. CORT113176 treatment prevents epileptic seizures in both sexes of mice

[0116] Seizures are a known symptom of juvenile HD (JHD), a form of HD affecting children and adolescents, and this characteristic was recapitulated in the R6 / 2 mouse model. 25 All epileptic seizures observed during the experiment were recorded. According to the Racine scale, these seizures were all tonic-clonic seizures. 15 Seizures occurred most frequently in vehicle-treated female HD mice, whereas no seizures were observed in CORT113176-treated female HD mice ( Figure 1D Overall, seizures were less common in male HD mice, although vehicle-treated HD mice also had slightly higher frequencies of seizures compared to CORT113176-treated male HD mice ( Figure 1D Most of the seizures in CORT113176-treated HD mice occurred near the end of the five weeks (day 32), whereas seizures in vehicle-treated HD animals occurred throughout the entire five-week study ( Figure 1E and 1F ).

[0117] The activity of astrocytes and microglia was assessed by GFAP and Iba1 staining, respectively. In the striatum, GFAP immunoreactivity was significantly increased in both male and female HD mice compared with wild-type mice ( Figure 2A, HD: and 2B, HD), and CORT113176 treatment normalized GFAP levels in male mice but not in female mice ( Figure 2A A significant genotype effect of Iba1 immunoreactivity was observed in the striatum of both male and female mice.

[0118] Next, we assessed astrocyte and microglial markers in the hippocampus. In this brain region, GFAP staining showed an overall trend associated with genotype ( Figure 2C , HD), and the GFAP staining intensity of vehicle-treated male HD mice was significantly reduced compared with that of wild-type mice ( Figure 2C Similar to the striatum, CORT113176 treatment normalized the HD effect ( Figure 2C ). The graph of GFAP staining intensity in female mice is shown in Figure 2D In the hippocampus of male HD mice, Iba1 staining intensity tended to increase after CORT113176 treatment ( Figure 2E , CORT113176). Example 2

[0119] The results disclosed in Example 1 demonstrated unexpected sex differences. To replicate and further characterize the potential beneficial effects of CORT113176 treatment in a larger group of male R6 / 2 mice, these results confirmed the positive effects of CORT113176 administration on grip strength, clasping behavior, and seizure activity. CORT113176 treatment delays multiple motor symptoms in male HD mice

[0120] Consistent with the results discussed above, CORT113176 increased grip strength and reduced clasping scores compared to vehicle-treated mice. Only one seizure was observed in CORT113176-treated HD mice (occurring near the end of the study), whereas several vehicle-treated HD mice experienced seizures early in the study. CORT113176 treatment reduces mutant huntingtin aggregate formation in the striatum and hippocampal CA1 region

[0121] The formation of mHtt aggregates was assessed, as they are considered a hallmark of the HD phenotype. In the striatum, the number of aggregates was significantly increased in vehicle-treated HD mice compared to wild-type mice. CORT113176 treatment significantly reduced the number of mHtt aggregates, and the aggregate size was similar in vehicle-treated and CORT113176-treated HD mice ( Figure 3A and Figure 3B ).

[0122] In the CA1 region of the hippocampus, the total number of aggregates was significantly increased in HD mice compared to wild-type mice. CORT113176-treated mice had a significant decrease in the number of aggregates in this brain region compared to vehicle-treated HD mice. Furthermore, CORT113176-treated mice had smaller aggregates than vehicle-treated HD mice, resulting in a smaller total area of ​​aggregates in the CA1 region. Discussion and Summary

[0123] In this study, we evaluated the efficacy of CORT113176, a selective GRM, in ameliorating HD symptoms in the R6 / 2 mouse model. In two independent studies, we showed that CORT113176 delayed multiple motor and neuropathological symptoms of HD in male mice.

[0124] In mice, we observed that CORT113176 treatment alleviated multiple HD-related symptoms. Thus, CORT113176 treatment partially improved grip strength and significantly reduced clasping scores. Furthermore, CORT113176 treatment prevented epileptic seizures, which are common in JHD and R6 / 2 models. 16-17 CORT113176 also reduced protein aggregation in the brains of male R6 / 2 mice (female mice were not evaluated). In summary, CORT113176 has a significant therapeutic effect on the CNS, especially in male mice.

[0125] All patents, patent publications, publications, and patent applications cited in this specification are incorporated herein by reference in their entirety, just as if each individual publication or patent application was specifically and individually incorporated by reference. In addition, although the present invention has been described in detail by way of illustration and example for purposes of illustration, it will be readily apparent to those skilled in the art, based on the teachings of this disclosure, that certain changes and modifications may be made without departing from the spirit or scope of the appended claims. References 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(PtA):308-17. 6. Morton AJ, Lagan MA, Skepper JN, Dunnett SB. Progressive formation of inclusions in thestriatum 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 hERGinhibition 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 pilepsy. Epilepsy Behav Rep. 2021;16:100470. 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 of treating a patient suffering from Huntington's disease (HD), the method comprising administering to the patient an amount of a heteroaryl ketone-fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro-fused azadecalin GRM effective to treat HD.

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

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

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

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

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

7. The method of claim 5, wherein the motor symptoms of HD are selected from the group consisting of: involuntary jerking movements (spasticity); involuntary writhing movements (chorea); muscle contractions or stiffness (dystonia); tremor; slowed or abnormal eye movements; impaired muscle strength; impaired grip; impaired gait (i.e., difficulty walking); impaired balance; impaired swallowing; impaired respiratory function; impaired posture; impaired ability to stand upright; impaired ability to maintain head position; and impaired speech. in, Impairment is determined by comparison with the ability to perform motor activities at baseline (e.g., before the onset of HD symptoms, or at the time of initial diagnosis of HD symptoms). wherein said administering an effective amount of said heteroaryl ketone-fused azadecalin GRM or said octahydro-fused azadecalin GRM is effective in treating the motor symptoms of HD.

8. The method of claim 6, wherein the symptoms of HD include seizures, and the treatment is effective to reduce the frequency of the seizures.

9. The method of claim 6, wherein the symptoms of HD include seizures, and the treatment is effective to reduce the frequency or severity of the seizures.

10. The method of claim 6, wherein the symptom of HD is a neurological or psychological symptom selected from the group consisting of: forgetfulness; other memory loss; confusion; impaired speech; impaired attention; impaired speed of comprehension; delirium; hallucinations; paranoia; depression; anxiety; apathy; and rapid or unexplained changes in mood, in, Impairment is determined by comparison with the ability or level of neurological or psychological activity or symptoms at baseline (e.g., before the onset of HD symptoms, or at the time of initial diagnosis of HD symptoms), wherein said administering 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 comprises a chemical structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl, C 3-8 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 atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C 3-8 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 4 R 2c group substitution; Alternatively, two R attached to the same carbon 2 The 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 atoms and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted by 1 to 3 R 2d group substitution; R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 2c Independently selected from the following groups: hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN and NR 2a R 2b ; Each R 2d independently selected from the group consisting of hydrogen and C 1-6 Alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1 to 4 R 3a group substitution; Each R 3a Independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and Subscript n is an integer from 0 to 3; or its salts and isomers.

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

13. The method of any one of claims 1 to 10, wherein the GRM is an octahydrofused azadecalin GRM, and the GRM comprises a chemical structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, C 3-8 Cycloalkyl; Ring J is selected from the group consisting of an aryl ring and a heteroaryl ring, wherein the heteroaryl ring has 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms 3-8 Heterocycloalkyl, wherein the heteroatoms are each independently selected from the group consisting of N, O, and S; Alternatively, two R on adjacent ring atoms 2 The groups combine to form a heterocycloalkyl ring having 5 to 6 ring atoms and 1 to 3 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1-3 R 2c group substitution; R 2a 、R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 3a are independently halogen; and subscript n is an integer from 0 to 3, or its salts and isomers.

14. The method of claim 13, wherein the octahydrofused azadecalin GRM is zavakoline (which is ((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:

15. A pharmaceutical composition for treating Huntington's disease (HD) or a symptom thereof, comprising a pharmaceutically acceptable excipient and a nonsteroidal glucocorticoid receptor modulator (GRM) compound comprising a heteroaryl ketone-fused azadecalin structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl, C 3-8 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 atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C 3-8 Heterocycloalkyl, wherein Heterocycloalkyl is optionally substituted with 1 to 4 R 2c group substitution; Alternatively, two R attached to the same carbon 2 The 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 atoms and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted by 1 to 3 R 2d group substitution; R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 2c Independently selected from the following groups: hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN and NR 2a R 2b ; Each R 2d independently selected from the group consisting of hydrogen and C 1-6 Alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1 to 4 R 3a group substitution; Each R 3a Independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and Subscript n is an integer from 0 to 3; or its salts and isomers.

16. The pharmaceutical composition of claim 15, wherein the nonsteroidal GRM comprising a heteroaryl ketone-fused azadecalin structure is dazuclofen (which is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone) having the following structure:

17. A pharmaceutical composition for treating Huntington's disease (HD) or a symptom thereof, comprising a pharmaceutically acceptable excipient and a nonsteroidal glucocorticoid receptor modulator (GRM) compound comprising an octahydrofused azadecalin structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide and C 3-8 Cycloalkyl; Ring J is selected from the group consisting of an aryl ring and a heteroaryl ring, wherein the heteroaryl ring has 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms 3-8 Heterocycloalkyl, wherein the heteroatoms are each independently selected from the group consisting of N, O, and S; Alternatively, two R on adjacent ring atoms 2 The groups combine to form a heterocycloalkyl ring having 5 to 6 ring atoms and 1 to 3 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1-3 R 2c group substitution; R 2a 、R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 3a are independently halogen; and subscript n is an integer from 0 to 3, or its salts and isomers.

18. The pharmaceutical composition of claim 17, wherein the nonsteroidal GRM compound comprising an octahydrofused azadecalin GRM is zavakolan (which is ((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:

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

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

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

22. The pharmaceutical composition according to claim 17, for use in treating symptoms of HD, 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 HD or a symptom thereof.

25. The use of claim 23 or the use of claim 24, wherein the treating HD comprises treating a symptom of HD.

26. The use according to any one of claims 23 to 25, wherein the treating HD comprises treating elevated Cortisol levels in a patient suffering from HD.

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

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

29. 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 jerking movements (spasticity); involuntary writhing movements (chorea); muscle contractions or stiffness (dystonia); tremor; slowed or abnormal eye movements; impaired muscle strength; impaired grip; impaired gait (i.e., difficulty walking); impaired balance; impaired swallowing; impaired respiratory function; impaired posture; impaired ability to stand upright; impaired ability to maintain head position; and impaired speech.

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

31. The use according to any one of claims 23 to 25, wherein the treating HD comprises treating a neurological or psychological symptom of HD selected from the group consisting of amnesia; other memory loss; confusion; impaired speech; impaired attention; impaired speed of comprehension; delirium; hallucinations; paranoia; depression; anxiety; apathy; and rapid or unexplained changes in mood.

32. The use according to any one of claims 23 to 31, wherein the GRM is a heteroaryl ketone fused azadecalin GRM comprising a chemical structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl and C 3-8 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 atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C 3-8 Heterocycloalkyl, wherein The heterocycloalkyl group is optionally substituted with 1 to 4 R 2c group substitution; Alternatively, two R attached to the same carbon 2 The 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 atoms and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted by 1 to 3 R 2d group substitution; R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 2c Independently selected from the following groups: hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN and NR 2a R 2b ; Each R 2d independently selected from the group consisting of hydrogen and C 1-6 Alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1 to 4 R 3a group substitution; Each R 3a Independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and Subscript n is an integer from 0 to 3; or its salts and isomers.

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

34. The use according to any one of claims 23 to 31, wherein the GRM is an octahydrofused azadecalin GRM comprising a chemical structure having the formula: in R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted by 1 to 4 heteroatoms each independently selected from R 1a The group substitution; Each R 1a Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide and C 3-8 Cycloalkyl; Ring J is selected from the group consisting of an aryl ring and a heteroaryl ring, wherein the heteroaryl ring has 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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 SR 2a 、S(O)R 2a 、S(O)2R 2a 、C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms 3-8 Heterocycloalkyl, wherein the heteroatoms are each independently selected from the group consisting of N, O, and S; Alternatively, two R on adjacent ring atoms 2 The groups combine to form a heterocycloalkyl ring having 5 to 6 ring atoms and 1 to 3 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1-3 R 2c group substitution; R 2a 、R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; Each R 3a are independently halogen; and subscript n is an integer from 0 to 3, or its salts and isomers.

35. The use according to claim 34, wherein the non-steroidal GRM compound comprising an octahydrofused azadecalin GRM is zavakolan (which is ((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:

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