Corticotropin releasing factor receptor antagonists

Abstract

To provide a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof.SOLUTION: The present invention provides a method comprising administering a pharmaceutical composition comprising the compound of the formula below, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered at a dose between about 50 mg / day and about 1600 mg / day.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 545,406, filed August 14, 2017, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Corticotropin-releasing factor (CRF), a 41-amino acid peptide, is the primary physiological peptide that regulates the secretion of proopiomelanocortin (POMC)-derived peptides from the anterior pituitary gland. In addition to its endocrine role in the pituitary gland, immunohistochemical localization of CRF has revealed that the hormone is widely distributed in the central nervous system outside the hypothalamus and exerts a wide range of autonomic, electrophysiological, and behavioral effects, consistent with its role as a neurotransmitter or neuromodulator in the brain. CRF has also been shown to play an important role in coordinating immune system responses to physiological, psychological, and immunological stressors. Summary of the Invention

[0003] The present invention provides novel pharmaceutical compositions comprising 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using such pharmaceutical compositions for the treatment of congenital adrenal hyperplasia (CAH).

[0004] In one embodiment, the disclosure provides a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering to the subject compound 1,

[0005] [ka] or a pharma- ceutical composition comprising the compound 1, wherein Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day.

[0006] In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 1200 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 1000 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 800 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 100 mg / day to about 600 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 400 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day.

[0007] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is in the form of microparticles. In some embodiments, the microparticles have an average size of about 1 μm to about 20 μm. In some embodiments, the microparticles have an average size of about 5 μm to about 15 μm. In some embodiments, the microparticles have an average size of less than about 10 μm.

[0008] In some embodiments, the pharmaceutical composition is in the form of a capsule or tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a soft gelatin capsule. In some embodiments, the capsule is formed using a material selected from the group consisting of natural gelatin, synthetic gelatin, pectin, casein, collagen, proteins, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, and any combination thereof.

[0009] In some embodiments, the pharmaceutical composition does not contain additional excipients. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients.

[0010] In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 100 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0011] In some embodiments, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 2 to about 6 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 3 to about 5 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 6 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 5 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 4 hours.max It takes about 3 hours.

[0013] In some embodiments, the pharmaceutical composition is administered under fed conditions. In some embodiments, the pharmaceutical composition is administered under fasted conditions. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered three times daily.

[0014] In some embodiments, the method further comprises administering a glucocorticoid. In some embodiments, the dosage of the glucocorticoid is reduced when compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the dosage of the glucocorticoid is reduced from supraphysiological to physiological amounts. In some embodiments, the amount of glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%.

[0015] In some embodiments, a condition associated with high-dose glucocorticoid therapy is reduced. In some embodiments, the condition associated with high-dose glucocorticoid therapy is obesity, insulin resistance, metabolic disorders, hypertension, cardiovascular disease, or osteoporosis. In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.

[0016] In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the hydrocortisone is administered at a dose of less than about 15 mg / day. In some embodiments, the hydrocortisone is administered at a dose of less than about 10 mg / day. In some embodiments, the hydrocortisone is administered at a dose of less than about 5 mg / day.

[0017] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered simultaneously. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 24 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 8 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 2 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 30 minutes.

[0018] In some embodiments, the method further comprises administering a mineralocorticoid, hi some embodiments, the mineralocorticoid is fludrocortisone.

[0019] In some embodiments, the pharmaceutical composition is administered at bedtime. In some embodiments, the pharmaceutical composition is administered up to about 4 hours before going to bed. In some embodiments, the pharmaceutical composition is administered up to about 2 hours before going to bed. In some embodiments, the pharmaceutical composition is administered up to about 30 minutes before going to bed. In some embodiments, the pharmaceutical composition is administered at night. In some embodiments, the pharmaceutical composition is administered at night around 10 p.m. In some embodiments, the pharmaceutical composition is administered at or before the expected time of circadian release of adrenocorticotropic hormone (ACTH). In some embodiments, the pharmaceutical composition is administered about 3-4 hours before the expected time of circadian release of adrenocorticotropic hormone (ACTH).

[0020] In some embodiments, the CAH is classical CAH. In some embodiments, the CAH is non-classical CAH.

[0021] In one embodiment, the disclosure provides a method of treating congenital adrenal hyperplasia (CAH) in a subject in need of such treatment, comprising: (i) measuring hormone levels in a subject in need of such treatment; (ii) administering Compound 1;

[0022] [ka] or a pharma- ceutical acceptable salt or solvate thereof; and (iii) repeating steps (i) and (ii) until the hormone levels reach a pre-determined range, followed by maintenance therapy with daily administration of compound 1.

[0023] In some embodiments, the hormone is 17α-hydroxyprogesterone (17-OHP), adrenocorticotropic hormone (ACTH), testosterone, or androstenedione. In some embodiments, the hormone is 17-OHP, and the predetermined range is about 200 ng / dL to about 400 ng / dL. In some embodiments, the hormone is ACTH, and the predetermined range is less than about 100 pg / mL. In some embodiments, the hormone is testosterone, and the predetermined range is about 14 ng / dL to about 76 ng / dL. In some embodiments, the hormone is androstenedione, and in men, the predetermined range is about 30 ng / dL to about 150 ng / dL. In some embodiments, the hormone is androstenedione, and in women, the predetermined range is about 40 ng / dL to about 200 ng / dL.

[0024] In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 1600 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 1200 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 1000 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 800 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 600 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day to about 400 mg / day. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 200 mg / day.

[0025] In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 1200 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 1000 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 800 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 600 mg / day. In some embodiments, compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day to about 400 mg / day. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of 50 mg / day to 200 mg / day. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at a dose of about 50 mg / day.

[0026] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is in the form of microparticles. In some embodiments, the microparticles have an average size of about 1 μm to about 20 μm. In some embodiments, the microparticles have an average size of about 5 μm to about 15 μm. In some embodiments, the microparticles have an average size of less than about 10 μm.

[0027] In some embodiments, Compound 1 is formulated into a pharmaceutical composition in the form of a capsule or tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a soft gelatin capsule. In some embodiments, the capsule is formed using a material selected from the group consisting of natural gelatin, synthetic gelatin, pectin, casein, collagen, proteins, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, and any combination thereof.

[0028] In some embodiments, the pharmaceutical composition does not contain additional excipients. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutical acceptable excipients. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutical acceptable excipients.

[0029] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0030] In some embodiments, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0031] In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 2 to about 6 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 3 to about 5 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 6 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 5 hours. max In some embodiments, the T of Compound 1 in a subject provided by the pharmaceutical composition is about 4 hours.max It takes about 3 hours.

[0032] In some embodiments, the pharmaceutical composition is administered under fed conditions. In some embodiments, the pharmaceutical composition is administered under fasted conditions. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered three times daily.

[0033] In some embodiments, the method further comprises administering a glucocorticoid. In some embodiments, the amount of glucocorticoid administered is reduced when compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the amount of glucocorticoid used is reduced from supraphysiological to physiological amounts. In some embodiments, the amount of glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%.

[0034] In some embodiments, the symptoms associated with high-dose glucocorticoid therapy are reduced. In some embodiments, the symptoms associated with high-dose glucocorticoid therapy are obesity, insulin resistance, metabolic disorders, hypertension, cardiovascular disease, or osteoporosis. In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone. In some embodiments, the glucocorticoid is hydrocortisone.

[0035] In some embodiments, the hydrocortisone is administered at a dose of less than about 15 mg / day. In some embodiments, the hydrocortisone is administered at a dose of less than about 10 mg / day. In some embodiments, the hydrocortisone is administered at a dose of less than about 5 mg / day.

[0036] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered simultaneously. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 24 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 8 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 2 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially within 30 minutes.

[0037] In some embodiments, the method further comprises administering a mineralocorticoid, hi some embodiments, the mineralocorticoid is fludrocortisone.

[0038] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at bedtime. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered up to about 4 hours before going to bed. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered up to about 2 hours before going to bed. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered up to about 30 minutes before going to bed. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at night. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at night at 10 p.m.

[0039] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered at or before the expected time of diurnal release of adrenocorticotropic hormone (ACTH). In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered about 3 to 4 hours before the expected time of diurnal release of adrenocorticotropic hormone (ACTH).

[0040] In some embodiments, the CAH is classical CAH. In some embodiments, the CAH is non-classical CAH.

[0041] In some embodiments, the subject in need of said treatment is about 12 to about 20 years of age.

[0042] In one embodiment, the disclosure provides a method of ameliorating hyperandrogenism in a subject in need of treatment, comprising administering to a subject a compound of formula I,

[0043] [ka] or a pharma- ceutical acceptable salt or solvate thereof, wherein Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, the hyperandrogenism is selected from the group consisting of acne, hirsutism, and alopecia.

[0044] In one embodiment, the disclosure provides a method of treating menstrual irregularities, ovulation disorders, or infertility in a subject in need thereof, comprising administering to said subject compound 1,

[0045] [ka] or a pharma- ceutical composition comprising the compound 1, wherein Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day.

[0046] The present disclosure provides a method for ameliorating a metabolic condition in a subject in need thereof, comprising administering to said subject a compound of formula (I):

[0047] [ka] or a pharma- ceutical acceptable salt or solvate thereof, wherein Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, the metabolic symptom is selected from the group consisting of weight, BMI, waist circumference, blood pressure, and glycemic control.

[0048] In one embodiment, the disclosure provides a method of improving the quality of life of a subject in need of treatment, comprising administering to a subject a compound of formula I,

[0049] [ka] or a pharma- ceutical composition comprising the compound 1, wherein compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day, and treatment results in improved quality of life.

[0050] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0051] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0052] [Figure 1]FIG. 1 shows Compound 1 in CAH patients after 14 days of once daily dosing at each dose level. [Diagram 2] FIG. 2 shows the attenuation of ACTH in different subjects by administration of Compound 1. [Diagram 3] FIG. 3 shows the reduction in 17-OHP by administration of Compound 1. [Figure 4] FIG. 4 shows the reduction in androstenedione with administration of the compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] CRF has been associated with psychiatric and neurological disorders, including depression and anxiety, as well as Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol abuse, substance abuse, and abuse-related withdrawal, obesity, metabolic syndrome, congenital adrenal hyperplasia (CAH), Cushing's disease, hypertension, stroke, irritable bowel syndrome, stress-induced gastric ulcers, premenstrual syndrome, psychosexual dysfunction, preterm labor, inflammatory diseases, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary or ectopic pituitary tumors, chronic fatigue syndrome, and fibromyalgia.

[0054] CRF receptor subtypes CRF1 and CRF2 have been identified, but their heterogeneous distribution in the brain suggests that they may have diverse functions. For example, CRF1 receptors, which are widely distributed in the brain, are strongly associated with emotionality associated with exposure to environmental stressors. Importantly, CRF1 receptors appear to mediate and select for anxiety-provoking behaviors, whereas CRF2 receptors do not. The more discrete distribution in the septallhypothalmic region, as well as the availability of alternative endogenous ligands, suggest a distinct functional role for CRF2 receptors. For example, a novel CRF family neuropeptide with preferential affinity for CRF2 receptors compared to CRF1 receptors has been reported to suppress appetite without the behavioral activation profile observed with selective receptor agonism by CRF1. In other cases, receptor agonism by CRF2 results in effects similar to those reported for CRF1 antagonists and CRF1 gene deletion. For example, while CRF2 agonists have been proposed as anti-obesity drugs, CRF1 antagonists may also be important treatments for obesity.

[0055] Treatment of CAH, from diagnosis in infancy through adulthood, is based on normalizing hormone and steroid levels with a variety of pharmacologic therapies. Glucocorticoids are the current standard of care for CAH, and are used to both correct the deficiency of endogenous cortisol and to reduce the rise in ACTH from the pituitary gland that increases androgen production. Unlike Addison's disease (adrenal insufficiency), where cortisol replacement is sufficient to treat CAH, treatment also requires reducing ACTH production to regulate subsequent androgen excess. Thus, the goals of glucocorticoid therapy include preventing virilization and menstrual disorders in women through cortisol replacement and ACTH suppression. In patients with salt-wasting CAH, mineralocorticoid replacement is required to achieve normal plasma renin activity to maintain steady-state blood pressure, electrolyte balance, and volume status.

[0056] A glucocorticoid treatment program is required to support normal physiological function and also to ensure that sufficient cortisol is available during events that may induce a strong stress response (e.g., intercurrent illness, exercise, hypotension). Careful monitoring is also required to avoid the development of Addison's syndrome due to inadequate treatment. Overtreatment with mineralocorticoids can cause hypertension, while inadequate treatment can result in hypotension, salt wasting, fatigue, and increased glucocorticoid requirements. Typical laboratory tests aimed at monitoring the effectiveness of treatment include measurements of plasma levels of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes.

[0057] Adult CAH patients have an increased prevalence of cardiovascular risk factors, including obesity, hypertension, and insulin resistance. A large cohort study of pediatric and adult CAH patients (n=244) found that patients prescribed various glucocorticoid treatment regimens frequently developed hormonal dysregulation and the adverse events mentioned above. Treatment of CAH involves attempts to normalize cortisol deficiency with glucocorticoids (usually hydrocortisone for children, but often more potent agents with narrow therapeutic indexes such as dexamethasone for adults) and, if necessary, with mineralocorticoids (usually fludrocortisone) in cases of salt-wasting CAH. However, the glucocorticoid doses required to achieve adequate suppression of excess androgens are usually much higher than the usual physiologic doses used for cortisol replacement alone in patients with Addison's disease. This increased exposure to glucocorticoids may lead to increased cardiovascular risk factors, glucose intolerance, and bone mineral loss in CAH patients.

[0058] CRF is believed to be the primary physiological regulator of basal and stress-induced release of adrenocorticotropic hormone ("ACTH"), β-endorphin, and other proopiomelanocortin ("POMC")-derived peptides from the anterior pituitary gland. Secretion of CRF causes release of ACTH from corticotropes in the anterior pituitary gland via binding to the CRF1 receptor, a member of the class B family of G protein-coupled receptors.

[0059] Given the physiological importance of CRF1, the development of biologically active small molecules that have significant CRF receptor binding activity and can antagonize the CRF1 receptor remains desirable and is the subject of ongoing research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and substance abuse.

[0060] The pituitary hormone ACTH stimulates cholesterol uptake, drives pregnenolone synthesis, and initiates steroidogenesis in the adrenal glands under the control of corticotropin-releasing factor (CRF) secreted from the hypothalamus. The adrenal cortex is made up of three regions, each producing a different class of hormone, but much of the hormone production is driven by ACTH, which mobilizes cholesterol through this pathway. Deficiency of these enzymes as a result of mutation or deletion increases the concentration of their substrates. In the most common form of CAH, caused by mutation or deletion in the 21-hydroxylase gene (CYP21 A2), potent androgens are produced by the adrenal glands through the accumulation of the steroid precursors progesterone and 17-hydroxyprogesterone (17-OHP). In such cases, plasma concentrations of 17-OHP can reach 10-1000 times normal concentrations. This increase results in overproduction of androgens, especially androstenedione, testosterone, and dihydroxytestosterone, causing virilization in women. Furthermore, the deficiency of 21-hydroxylase in CAH results in insufficient biosynthesis of glucocorticoids and mineralocorticoids, especially cortisol and aldosterone. Cortisol is an essential negative feedback regulator of CRF secretion in the hypothalamus and ACTH release in the pituitary. Insufficient glucocorticoid synthesis and release removes inhibitions on the hypothalamus and pituitary, resulting in increased ACTH levels. This excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis, resulting in adrenal hyperplasia.

[0061] In one embodiment, a CRF receptor antagonist useful in the treatment of CAH is 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(l-ethylpropyl)-2,5-dimethylpyrazolo(l,5-a)pyrimidine.

[0062] Specific Definitions Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein. Certain preferred methods, devices, and materials are described below.

[0063] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" refers to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

[0064] Use of the term "about" implies that the value contains the standard level of error for the device or method being employed to determine the value.

[0065] Use of the term "or" in the claims is intended to mean "and / or" unless expressly indicated to refer to only alternatives or unless the alternatives are mutually exclusive, although the present disclosure supports this definition of "and / or."

[0066] The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," are open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0067] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent systemically or locally directly into or onto a target tissue, or administering a therapeutic agent to a patient to allow the therapeutic agent to have a positive effect on the target tissue. "Administering" a pharmaceutical composition may be accomplished by injection, topical administration, and oral administration, alone or in combination with other known techniques, or by other methods.

[0068] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0069] The term "pharmaceutical composition" refers to a composition that contains at least one active ingredient, such as Compound 1, and is therefore suitable for testing a particular efficacy outcome in a mammal (e.g., but not limited to, a human). Those of skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired efficacy outcome based on the needs of the artisan.

[0070] The term "supraphysiological" amounts refers to elevated hormone levels compared to the average values ​​found in healthy individuals.

[0071] The term "physiologic amount" refers to the average hormone levels found in healthy individuals.

[0072] A "therapeutically effective amount" or "effective amount," as used herein, refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, said response including one or more of the following: (1) prevention of disease, e.g., prevention of a disease, disorder, or disorder in an individual who may be susceptible to the disease, disorder, or disorder but has not yet experienced or exhibited the symptoms or symptomology of the disease, (2) inhibition of disease, e.g., inhibition of a disease, disorder, or disorder (i.e., arresting further occurrence of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, disorder, or disorder, and (3) amelioration of disease, e.g., amelioration of a disease, disorder, or disorder (i.e., reversal of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, disorder, or disorder.

[0073] The terms "treat," "treated," "treatment," or "treating," as used herein, refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, aimed at preventing or delaying (reducing) an undesirable physiological condition, disorder, or disease, or obtaining a beneficial or desired clinical outcome. For purposes herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the abnormality, disorder, or disease; stabilization (i.e., not worsening) of the abnormality, disorder, or disease state; delayed onset or delayed progression of the abnormality, disorder, or disease; amelioration of the abnormality, disorder, or disease state; and remission (which may be partial or complete), which may be detectable or undetectable, or may be an enhancement or amelioration of the abnormality, disorder, or disease. Treatment includes eliciting a clinically meaningful response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival in the absence of treatment. Prophylactic benefits of treatment include prevention of the abnormality, slowing the progression of the abnormality, stabilizing the abnormality, or reducing the likelihood of the abnormality occurring. As used herein, "treat," "treated," "treatment," or "treating" also includes prevention in some embodiments.

[0074] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will immediately occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are covered thereby.

[0075] compound Disclosed herein is 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine (or 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine), its pharma- ceutically acceptable salts, and / or solvates thereof.

[0076] [ka] In some embodiments, 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine is referred to as compound 1. In some embodiments, 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine is referred to as compound 1.

[0077] Pharmaceutical Compositions Disclosed herein are pharmaceutical compositions comprising Compound 1, its pharma- ceutically acceptable salts, and / or solvates thereof.

[0078] Dosage form In some embodiments, the pharmaceutical compositions described herein are provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of Compound 1 suitable for administration to an animal subject, preferably a mammalian subject, in a single dose in accordance with good medical practice. The preparation of a single or unit dosage form, however, does not mean that the dosage form is administered once per day or once per treatment course. Such dosage forms are contemplated to be administered once, twice, three or more times per day, and may be administered as an infusion over a period of time (e.g., over about 30 minutes to about 2 to 6 hours) or as a continuous infusion, and may be given more than once during the course of treatment, although a single dose is not specifically excluded.

[0079] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose, as well as the appropriate duration and frequency of administration, will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Usually, an appropriate dose and treatment regimen provides a sufficient amount of the composition to achieve a therapeutic and / or prophylactic effect, such as an increased frequency of complete or partial remission, or an increased disease-free and / or overall survival time, or an improved clinical outcome, such as a reduced severity of symptoms. The optimal dose is usually determined using experimental models and / or clinical trials. The optimal dose is determined based on the patient's size, weight, or blood volume.

[0080] In some embodiments, the pharmaceutical compositions described herein are formulated as oral dosage forms. Suitable oral dosage forms include, for example, tablets, pills, sachets, and capsules. In some embodiments, the pharmaceutical compositions further comprise one or more pharma- ceutical acceptable excipients. For a list of pharma-ceutical acceptable excipients, see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st See Ed. Mack Pub. Co., Easton, PA (2005).

[0081] Capsules In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a hard gel capsule. In some embodiments, the pharmaceutical composition is formulated as a soft gel capsule.

[0082] In some embodiments, the capsule is formed using the following materials, including but not limited to natural gelatin, synthetic gelatin, pectin, casein, collagen, proteins, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, or any combination thereof. In some embodiments, the capsule is formed using preservatives, colorants, opacifiers, flavorings, sweeteners, sugars, gastroresistant materials, or any combination thereof. In some embodiments, the capsule is coated. In some embodiments, the coating covering the capsule includes but is not limited to an immediate release coating, a protective coating, an enteric or delayed release coating, a time release coating, a barrier coating, a seal coating, or any combination thereof. In some embodiments, the capsule herein is a hard capsule or a soft capsule. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is broken and the particulate matter is sprinkled on the soft food and swallowed without chewing. In some embodiments, the capsules are of different shapes and sizes. Examples of capsule shapes include, but are not limited to, round, oval, cylindrical, oblong, twist-off, and irregular shapes. The size of the capsule may vary based on the volume of particulate matter. In some embodiments, the size of the capsule is adjusted based on the volume of particulate matter and powder. Hard or soft gelatin capsules may be conventionally manufactured as single-body units containing the standard capsule shapes listed above. Single-body soft gelatin capsules may be provided in shapes such as oval, oblong, etc., typically with sizes of, for example, 3 to 22 mini (1 mini is equal to 0.0616 mL).The gelatin capsules may be manufactured conventionally, for example, as two-piece hard gelatin capsules that may be sealed or unsealed, usually of standard shape, and in a variety of standard sizes conventionally designated (000), (00), (0), (1), (2), (3), (4), and (5), with the highest number corresponding to the smallest size. In some embodiments, the pharmaceutical compositions (e.g., capsules) described herein are swallowed whole.

[0083] In some embodiments, the capsule comprises one or more pharma- ceutically acceptable excipients, hi some embodiments, the capsule comprises no additional excipients.

[0084] In some embodiments, a capsule for an insoluble drug substance is developed, manufactured, and marketed. In some embodiments, a drug substance is insoluble if its solubility in water is less than 0.002 mg / mL. In some embodiments, the capsule has a dosage strength of up to 200 mg. In some embodiments, the drug substance in the capsule is released immediately into the dissolution medium using USP Apparatus I. In some embodiments, the drug substance in the capsule is released immediately into the dissolution medium using USP Apparatus II.

[0085] tablet Poorly soluble drugs can be difficult to formulate using standard techniques such as high shear wet granulation. Optimal delivery of poorly soluble drugs may require complex techniques such as solid solution amorphous dispersions (hot melt extrusion or spray drying), nanoformulations, or lipid-based formulations. Hydrophobic drug substances may be considered poorly soluble according to USP criteria and are known to be difficult to granulate with water and other excipients. This is likely because most known excipients for immediate release formulations are water soluble or water swellable. Making tablets of poorly soluble high dose drug substances may require high concentrations of drug substance. However, as the drug concentration increases beyond a certain value, granulation formation may become even more difficult. Furthermore, at certain drug amounts, granulation formation may be impossible.

[0086] In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0087] In some embodiments, the tablet is made by compression, molding, or extrusion, optionally with one or more pharma- ceutically acceptable excipients. In some embodiments, the compressed tablet is made by compressing a mixture of Compound 1, optionally with pharma-ceutically acceptable excipients, into a free-flowing form. In some embodiments, the molded tablet is made by molding a mixture of Compound 1 powder moistened with an inert liquid diluent. In some embodiments, the tablet is made by hot melt extrusion. In some embodiments, the extruded tablet is made by forcing a mixture containing Compound 1 through an orifice or die under controlled conditions. In some embodiments, the tablet is a coated tablet or a scored tablet. In some embodiments, the tablet is formulated to provide delayed or controlled release of Compound 1. In some embodiments, the tablet is developed, manufactured, and marketed for an insoluble drug substance. In some embodiments, the drug substance is insoluble if its solubility in water is less than 0.002 mg / mL. In some embodiments, the tablet has a dose strength of up to 200 mg. In some embodiments, the drug substance in the tablet is released immediately into the dissolution medium using USP Apparatus I. In some embodiments, the drug substance in the tablet is released immediately into the dissolution medium using USP Apparatus II.

[0088] In some embodiments, the tablet size is less than about 1000 mg, less than about 800 mg, less than about 600 mg, less than about 400 mg, or less than about 200 mg. In some embodiments, the tablet has a dose strength of more than about 50 mg, more than about 100 mg, more than about 150 mg, more than about 200 mg, or more than about 250 mg. In some embodiments, the tablet size is less than about 1000 mg and the dose strength is more than about 50 mg. In some embodiments, the tablet size is less than 800 mg and the dose strength is more than about 100 mg. In some embodiments, the tablet size is less than 600 mg and the dose strength is more than about 150 mg. In some embodiments, the tablet size is less than 400 mg and the dose strength is more than about 200 mg. In some embodiments, the tablet size is less than 400 mg and the dose strength is 200 mg. In some embodiments, more than about 20% of the tablet dissolves in conventional solvents. In some embodiments, more than about 40% of the tablet dissolves in a conventional solvent. In some embodiments, more than about 50% of the tablet dissolves in a conventional solvent. In some embodiments, more than about 60% of the tablet dissolves in a conventional solvent. In some embodiments, more than about 70% of the tablet dissolves in a conventional solvent. In some embodiments, more than about 80% of the tablet dissolves in a conventional solvent. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 24 hours. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 12 hours. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 6 hours. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 3 hours. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 2 hours. In some embodiments, more than about 20% of the tablet dissolves in a conventional solvent in less than 60 minutes. In some embodiments, more than about 40% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 50% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 60% of the tablet dissolves in conventional solvents in less than 60 minutes. In some embodiments, more than about 70% of the tablet dissolves in conventional solvents in less than 60 minutes.In some embodiments, greater than about 80% of the tablet dissolves in conventional solvents in less than 60 minutes, hi some embodiments, greater than 70% of the tablet dissolves in conventional solvents in 60 minutes.

[0089] In some embodiments, the tablets are manufactured on a commercial scale.

[0090] In some embodiments, the tablet comprises one or more pharma- ceutically acceptable excipients.

[0091] In some embodiments, the tablet is coated with a coating material, such as a sealant. In some embodiments, the coating material is water soluble. In some embodiments, the coating material includes a polymer, a plasticizer, a pigment, or any combination thereof. In some embodiments, the coating material is in the form of a film coating, such as a gloss film, a pH independent film coating, an aqueous film coating, a dry powder film coating (e.g., a completely dry powder film coating), or any combination thereof. In some embodiments, the coating material is highly adhesive. In some embodiments, the coating material provides a low level of water permeability. In some embodiments, the coating material provides oxygen barrier protection. In some embodiments, the coating material allows for immediate disintegration for rapid release of Compound 1. In some embodiments, the coating material is colored, clear, or white. In some embodiments, the coating is an enteric coating. Exemplary coating materials include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, cellulose acetate trimellitate, sodium alginate, zein, and any combination thereof.

[0092] Pharmaceutically acceptable excipients In some embodiments, the pharmaceutical composition includes a pharma- ceutically acceptable excipient. In some embodiments, the composition does not include a pharma- ceutically acceptable excipient. The term "pharma- ceutically acceptable excipient," as used herein, means one or more compatible solid or encapsulating substances suitable for administration to a mammal. The term "compatible," as used herein, means that the components of the composition are miscible with the subject compounds and with each other under normal use conditions without interactions that would significantly reduce the pharmaceutical efficacy of the composition. In some embodiments, the pharma- ceutical acceptable excipient has a purity that is sufficiently high and a toxicity that is sufficiently low to be suitable for administration, preferably to an animal to be treated, preferably to a mammal to be treated.

[0093] Some examples of substances that can be used as pharma- ceutically acceptable excipients include: Amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is L-arginine. · Monosaccharides such as glucose (dextrose), arabinose, mannitol, fructose (levulose), and galactose. Cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose. ·Solid lubricants such as talc, stearic acid, magnesium stearate, and sodium stearyl fumarate. · Polymers such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol. · Emulsifiers such as polysorbates. Wetting agents such as sodium lauryl sulfate, Tween®, Span, alkyl sulfates, and alkyl ethoxylate sulfates. ·Diluents such as calcium carbonate, microcrystalline cellulose, calcium phosphate, starch, pregelatinized starch, sodium carbonate, mannitol, and lactose. · Binders such as starch (corn starch and potato starch), gelatin, sucrose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC). · Disintegrants such as starch and alginic acid. · Superdisintegrants such as Ac-Di-Sol, Croscarmellose Sodium, Sodium Starch Glycolate, and Crospovidone. · Glidants such as silicon dioxide. ·Coloring agents such as FD&C dyes. ·Sweetening agents and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors. · Preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate, phenylmercuric nitrate, parabens, and sodium benzoate. · Tonicity agents such as sodium chloride, potassium chloride, mannitol, and glycerin. · Antioxidants such as sodium bisulfite, acetone-sodium bisulfite, formaldehyde-sodium sulfoxylate, thiourea, and EDTA. ·pH adjusters such as NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. · Cryoprotectants such as sodium phosphate, potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates (e.g., glucose, mannitol, and dextran). · Cationic surfactants such as cetrimide, benzalkonium chloride, and cetylpyridinium chloride. · Anionic surfactants such as alkyl sulfates, alkyl ethoxylate sulfates, soaps, carboxylates, sulfates, and sulfonates. Non-ionic surfactants such as polyoxyethylene derivatives, polyoxypropylene derivatives, polyol derivatives, polyol esters, polyoxyethylene esters, poloxamers, glycol esters, glycerol esters, sorbitan derivatives, polyethylene glycols (PEG-40, PEG-50, PEG-55), and ethers of fatty alcohols. Carbohydrates and modified carbohydrates, lactose, alpha-lactose monohydrate, spray dried lactose and anhydrous lactose, starch and pregelatinized starch, sucrose, mannitol, sorbitol, cellulose, powdered cellulose, and organic substances such as microcrystalline cellulose. · Inorganic substances such as calcium phosphates (anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, and tricalcium phosphate). Co-processed diluents. · Surfactants such as sodium lauryl sulfate. Compression aid. ·Anti-tacking agents such as silicon dioxide and talc. content

[0094] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 100 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 90 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 50 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 40 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 30 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 20 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 10 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 5 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 5 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0095] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 1 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 5 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 90 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 10 mg to about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0096] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 100 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 90 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 20 mg to about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 100 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 90 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 30 mg to about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0098] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 100 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 90 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 40 mg to about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0099] In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 90 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and contains about 50 mg to about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0100] In some embodiments, the pharmaceutical composition comprises about 100 mg to about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg to about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0101] In some embodiments, the pharmaceutical composition comprises about 500 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 90 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 40 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0102] particle size In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule and comprises Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, in the form of microparticles. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 100 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 50 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 30 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 20 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 5 μm to about 15 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 1 μm to about 10 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 3 μm to about 10 μm. In some embodiments, the microparticles of Compound 1 have an average size of about 4 μm to about 9 μm.

[0103] In some embodiments, the microparticles of Compound 1 have an average size of less than about 100 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 80 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 60 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 50 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 40 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 30 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 20 μm. In some embodiments, the microparticles of Compound 1 have an average size of less than about 10 μm.

[0104] Pharmacokinetics In some embodiments, Compound 1 is administered to treat a subject max In some embodiments, Compound 1 is formulated as a capsule or tablet such that the T maxIn some embodiments, Compound 1 is formulated as a capsule or tablet such that the T max In some embodiments, Compound 1 is formulated as a capsule or tablet such that the T max It is formulated as a capsule or tablet so that the duration of action is about 3 to about 5 hours.

[0105] In some embodiments, Compound 1 is administered to treat a subject max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet to reduce the T max In some embodiments, Compound 1 is formulated as a capsule or tablet such that the T max In some embodiments, Compound 1 is formulated as a capsule or tablet such that the T max It is formulated as a capsule or tablet so that the onset of

[0106] stability The pharmaceutical compositions described herein are stable under a variety of storage conditions, including refrigerated, ambient, and accelerated conditions. Stable, as used herein, refers to a pharmaceutical composition that contains at least about 95% of the initial content of Compound 1 at the end of a given storage period, with impurities or related substances totaling less than about 5% (w / w). The percentage of impurities is calculated from the content of impurities relative to the content of Compound 1. Stability is assessed by HPLC or any other known testing method. In some embodiments, a stable pharmaceutical composition contains about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2.5% (w / w), about 2% (w / w), about 1.5% (w / w), about 1% (w / w), or about 0.5% (w / w) of impurities or related substances total. In other embodiments, a stable pharmaceutical composition contains about 5% (w / w) of impurities or related substances total. In yet another embodiment, the stable pharmaceutical composition comprises about 4% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition comprises about 3% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition comprises about 2% (w / w) total impurities or related substances. In yet another embodiment, the stable pharmaceutical composition comprises about 1% (w / w) total impurities or related substances.

[0107] Under refrigerated conditions, the pharmaceutical compositions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the refrigerated conditions are 5±5° C. In some embodiments, the refrigerated conditions are about 0° C., about 0.1° C., about 0.2° C., about 0.3° C., about 0.4° C., about 0.5° C., about 0.6° C., about 0.7° C., about 0.8° C., about 0.9° C., about 1° C., about 1.1° C., about 1.2° C., about 1.3° C., about 1.4° C., about 1.5° C., about 1.6° C., about 1.7° C., about 1.8° C., about 1.9° C., about 2° C., about 2.1° C., about 2.2° C., about 2.3° C., about 2.4° C., about 2.5° C., about 2.6° C., about 2.7° C., about 2.8° C., about 2.9° C., about 3.0° C., about 3.1° C., about 3.2° C., about 3.3° C., about 3.4° C., about 3.5° C., about 3.6° C., about 3.7° C., about 3.8° C., about 3.9° C., about 3.1° C., about 3.2° C., about 3.3° C., about 3.4° C., about .3°C, about 2.4°C, about 2.5°C, about 2.6°C, about 2.7°C, about 2.8°C, about 2.9°C, about 3°C, about 3.1°C, about 3.2°C, about 3.3°C, about 3.4°C, about 3.5°C, about 3.6°C, about 3.7°C, about 3.8°C, about 3.9°C, about 4°C, about 4.1°C, about 4.2°C, about 4.3°C, about 4.4°C, about 4.5°C, about 4.6°C, about 4.7°C, about 4.8°C, about 4. .9°C, about 5°C, about 5.1°C, about 5.2°C, about 5.3°C, about 5.4°C, about 5.5°C, about 5.6°C, about 5.7°C, about 5.8°C, about 5.9°C, about 6°C, about 6.1°C, about 6.2°C, about 6.3°C, about 6.4°C, about 6.5°C, about 6.6°C, about 6.7°C, about 6.8°C, about 6.9°C, about 7°C, about 7.1°C, about 7.2°C, about 7.3°C, about 7.4°C, about 7.5°C C, about 7.6° C, about 7.7° C, about 7.8° C, about 7.9° C, about 8° C, about 8.1° C, about 8.2° C, about 8.3° C, about 8.4° C, about 8.5° C, about 8.6° C, about 8.7° C, about 8.8° C, about 8.9° C, about 9° C, about 9.1° C, about 9.2° C, about 9.3° C, about 9.4° C, about 9.5° C, about 9.6° C, about 9.7° C, about 9.8° C, about 9.9° C, or about 10° C. Under accelerated conditions, the pharmaceutical compositions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months.Accelerated conditions for the pharmaceutical compositions described herein include temperatures at or above ambient temperature levels (e.g., 25±5° C.). In some cases, the accelerated conditions are about 40±2° C. In some cases, the accelerated conditions are about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., or about 60° C. Accelerated conditions for the pharmaceutical compositions described herein also include RH at or above ambient humidity levels (55±10% relative humidity (RH)). In other cases, the accelerated conditions are about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In other cases, the accelerated conditions are about 40° C. or 60° C. with ambient humidity. In yet other cases, the accelerated conditions are about 40±2° C. with humidity of 75±5% RH.

[0108] In some embodiments, the pharmaceutical composition is stable at about 5±5° C. to about 25±5° C. for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 5±5° C. for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 25±5° C. for at least 12 months. In one embodiment, the pharmaceutical composition is stable at about 5±5° C. for at least 24 months. In one embodiment, the pharmaceutical composition is stable at about 25±5° C. for at least 24 months.

[0109] Usage Disclosed herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the CAH is classical CAH. In some embodiments, the CAH is non-classical CAH. In some embodiments, the methods described herein result in a decrease in hormone levels. Such hormones include deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, aldosterone, pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone (17-OHP), dehydroepiandrosterone, androstenediol, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, estriol, and adrenocorticotropic hormone (ACTH). In some embodiments, the methods described herein result in a decrease in 17α-hydroxyprogesterone (17-OHP). In some embodiments, the methods described herein result in a decrease in adrenocorticotropic hormone (ACTH), also known as corticotropin.

[0110] Also provided herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising: (i) measuring hormone levels in a subject in need of said treatment; (ii) Compound 1,

[0111] [ka] or a pharma- ceutically acceptable salt or solvate thereof; (iii) repeating steps (i) and (ii) until the hormone levels reach a predetermined range, followed by maintenance therapy with daily administration of Compound 1; The method is disclosed, comprising:

[0112] In some embodiments, the hormone is 17α-hydroxyprogesterone (17-OHP), adrenocorticotropic hormone (ACTH), testosterone, or androstenedione.

[0113] In some embodiments, the hormone is 17-OHP and the predetermined range is about 200 ng / dL to about 400 ng / dL. In some embodiments, the hormone is 17-OHP and the predetermined range is less than about 400 ng / dL, less than about 350 ng / dL, less than about 300 ng / dL, less than about 250 ng / dL, or less than about 200 ng / dL.

[0114] In some embodiments, the hormone is ACTH and the predetermined range is less than about 100 pg / mL, hi some embodiments, the hormone is ACTH and the predetermined range is less than about 100 pg / mL, less than about 90 pg / mL, or less than about 80 pg / mL.

[0115] In some embodiments, the hormone is testosterone and the predetermined range is about 14 ng / dL to about 76 ng / dL. In some embodiments, the hormone is testosterone and the predetermined range is less than about 76 ng / dL, less than about 70 ng / dL, less than about 65 ng / dL, less than about 60 ng / dL, less than about 55 ng / dL, less than about 50 ng / dL, less than about 45 ng / dL, less than about 40 ng / dL, less than about 35 ng / dL, less than about 30 ng / dL, less than about 25 ng / dL, less than about 20 ng / dL, or less than about 15 ng / dL.

[0116] In some embodiments, the hormone is androstenedione and the predetermined range in men is about 30 ng / dL to about 200 ng / dL. In some embodiments, the hormone is androstenedione and the predetermined range in men is less than about 200 ng / dL, less than about 150 ng / dL, less than about 100 ng / dL, less than about 50 ng / dL, or less than about 30 ng / dL.

[0117] In some embodiments, the hormone is androstenedione and in women, the predetermined range is about 40 ng / dL to about 150 ng / dL. In some embodiments, the hormone is androstenedione and in women, the predetermined range is less than about 150 ng / dL, less than about 100 ng / dL, less than about 50 ng / dL, or less than about 40 ng / dL.

[0118] In some embodiments, the methods described herein include administering the pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, once a month, twice a month, three times a month, once a week, twice a week, three times a week, every other day, once a day, twice a day, three times a day, or four times a day. In some embodiments, the methods described herein administer Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, once a day. In some embodiments, the methods described herein administer Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, twice a day.

[0119] In some embodiments, the methods described herein include administration of about 1 mg to about 2000 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, per day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1500 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1400 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1300 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1200 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1100 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 1000 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 900 mg / day. In some embodiments, compound 1 is administered at a dose of about 50 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 60 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 70 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 80 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 90 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 100 mg / day to about 800 mg / day. In some embodiments, compound 1 is administered at a dose of about 100 mg / day to about 700 mg / day. In some embodiments, compound 1 is administered at a dose of about 100 mg / day to about 600 mg / day. In some embodiments, compound 1 is administered at a dose of 150 mg / day to about 600 mg / day. In some embodiments, compound 1 is administered at a dose of 200 mg / day to about 600 mg / day. In some embodiments, Compound 1 is administered at a dose of 200 mg / day to about 500 mg / day. In some embodiments, Compound 1 is administered at a dose of 200 mg / day to about 400 mg / day.

[0120] In some embodiments, compound 1 is administered at a dose of about 500 mg / day. In some embodiments, compound 1 is administered at a dose of about 400 mg / day. In some embodiments, compound 1 is administered at a dose of about 300 mg / day. In some embodiments, compound 1 is administered at a dose of about 200 mg / day. In some embodiments, compound 1 is administered at a dose of about 100 mg / day.

[0121] In some embodiments, about 100 mg to about 1600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 1600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 1200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 1000 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 800 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 100 mg to about 800 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 800 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 100 mg to about 600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 300 mg to about 600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 100 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 200 mg to about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, about 300 mg to about 400 mg of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered daily.

[0122] In some embodiments, less than about 2000 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1800 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 1000 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 800 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 600 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 500 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 400 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 300 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day. In some embodiments, less than about 200 mg of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, is administered per day.

[0123] In some embodiments, the methods described herein include administering a pharmaceutical composition described herein and the subject is in a fed state. In some embodiments, the methods described herein include administering a pharmaceutical composition described herein and the subject is in a fasted state.

[0124] In some embodiments, the methods described herein comprise administration of a pharmaceutical composition described herein at bedtime.

[0125] In some embodiments, the methods described herein include administration of a pharmaceutical composition described herein up to about 4 hours before going to bed. In some embodiments, the methods described herein include administration of a pharmaceutical composition described herein up to about 3 hours before going to bed. In some embodiments, the methods described herein include administration of a pharmaceutical composition described herein up to about 2 hours before going to bed. In some embodiments, the methods described herein include administration of a pharmaceutical composition described herein up to about 1 hour before going to bed. In some embodiments, the methods described herein include administration of a pharmaceutical composition described herein up to about 30 minutes before going to bed.

[0126] In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein.

[0127] In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 11 p.m. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 10 p.m. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 9 p.m. In some embodiments, the methods described herein comprise nighttime administration of a pharmaceutical composition described herein at about 8 p.m.

[0128] In some embodiments, the methods described herein comprise administration of a pharmaceutical composition described herein at or prior to the expected time of diurnal release of adrenocorticotropic hormone (ACTH). In some embodiments, the methods described herein comprise administration of a pharmaceutical composition described herein about 3 to 4 hours prior to the expected time of diurnal release of adrenocorticotropic hormone (ACTH). In some embodiments, the subject in need of said treatment is about 12 years of age to about 20 years of age.

[0129] In one embodiment, the disclosure provides a method of ameliorating hyperandrogenism in a subject in need of treatment, comprising: compound 1,

[0130] [ka] or a pharma- ceutical acceptable salt or solvate thereof, Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, the hyperandrogenism is selected from the group consisting of acne, hirsutism, and alopecia.

[0131] In one embodiment, the disclosure provides a method of treating menstrual irregularities, ovulation disorders, or infertility in a subject in need of such treatment, comprising: compound 1,

[0132] [ka] or a pharma- ceutical acceptable salt or solvate thereof, Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. The method is provided.

[0133] In one aspect, the disclosure provides a method of ameliorating a metabolic symptom in a subject in need thereof, comprising: compound 1,

[0134] [ka] or a pharma- ceutical acceptable salt or solvate thereof, Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day. In some embodiments, the metabolic symptom is selected from the group consisting of weight, BMI, waist circumference, blood pressure, and glycemic control.

[0135] In one embodiment, the disclosure provides a method of improving quality of life in a subject in need of treatment, comprising: compound 1,

[0136] [ka] or a pharma- ceutical acceptable salt or solvate thereof, Compound 1 is administered at a dose of about 50 mg / day to about 1600 mg / day; Treatment leads to improved quality of life, The method is provided.

[0137] Combination therapy Disclosed herein are methods of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering in combination Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and a glucocorticoid, In some embodiments, the amount of glucocorticoid administered is reduced as compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0138] In some embodiments, the methods described herein reduce the dosage of glucocorticoids from supraphysiological to physiological amounts.

[0139] In some embodiments, the methods described herein reduce a condition associated with high-dose glucocorticoid therapy, in some embodiments, the condition associated with high-dose glucocorticoid therapy is obesity, insulin resistance, metabolic disorders, hypertension, cardiovascular disease, or osteoporosis.

[0140] In some embodiments, the dosage of the glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 80, or about 90% when compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the dosage of the glucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% when compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0141] In some embodiments, the dosage of the glucocorticoid is reduced by about 1% to about 90%, about 1% to about 60%, about 1% to about 30%, about 1% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 15% to about 25%, about 20% to about 30%, about 5% to about 25%, about 20% to about 50%, about 30% to about 60%, or about 40% to about 70% when compared to a method that does not include administration of Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0142] In some embodiments, the glucocorticoid is administered at a dose of about 0.1 mg / day to about 25 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 20 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 15 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 12 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 10 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 9 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 8 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 7 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 6 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 5 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 4 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 3 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 1 mg / day to about 2 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 3 mg / day to about 13 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 5 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 8 mg / day to about 11 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 9 mg / day to about 12 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 9 mg / day to about 10 mg / day. In some embodiments, the glucocorticoid is administered at a dose of about 5 mg / day to about 10 mg / day.

[0143] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered simultaneously. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered in one pharmaceutical composition. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered in separate pharmaceutical compositions.

[0144] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered sequentially. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 24 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 12 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 8 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 6 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 4 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 2 hours. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 1 hour. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 30 minutes. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, and the glucocorticoid are administered within 10 minutes.

[0145] In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone, hi some embodiments, the glucocorticoid is hydrocortisone.

[0146] In some embodiments, the glucocorticoid is hydrocortisone and is administered at a dose less than the recommended dose of 15-25 mg / day.

[0147] In some embodiments, the glucocorticoid is prednisone and is administered at a dose less than the recommended dose of 5-7.5 mg / day.

[0148] In some embodiments, the glucocorticoid is prednisolone and is administered at a recommended dose of less than 4-6 mg / day.

[0149] In some embodiments, the glucocorticoid is dexamethasone and is administered at a recommended dose of less than 0.25-0.5 mg / day.

[0150] Disclosed herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, in combination with a glucocorticoid and, optionally, a mineralocorticoid. In some embodiments, the mineralocorticoid is fludrocortisone, and the dosage is less than the recommended dosage of 0.05-0.2 mg / day. EXAMPLES

[0151] The following examples further illustrate the present invention, but should not be construed as limiting the scope of the present invention in any way. In particular, the processing conditions are merely illustrative and can be easily modified by those skilled in the art.

[0152] All methods described herein can be carried out in any suitable order unless otherwise specified herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended only to facilitate understanding of the present invention and does not limit the scope of the present invention unless otherwise specified in the claims. Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0153] Example 1: Pharmaceutical Composition The pharmaceutical composition is prepared as a size 1 white hard gelatin capsule containing 200 mg of Compound 1 micronized to an average size of 10 μm or less. The pharmaceutical composition does not contain any additional excipients.

[0154] Example 2: Stability of pharmaceutical compositions Stability Data Overview The stability study of the pharmaceutical composition is summarized in Table 1. The pharmaceutical composition was prepared by filling pure Compound 1 without any excipients in size 0 capsules in three strengths (1 mg, 5 mg, and 50 mg), which were blister-packed in polyvinyl chloride (PVC)-based film.

[0155] No significant trends were identified among the three lots for any of the attributes evaluated through stability studies under long-term accelerated conditions.

[0156] [Table 1]

[0157] Stability Testing Protocol The stability testing protocols for the various pharmaceutical compositions are listed in Tables 2, 3, and 4.

[0158] [Table 2]

[0159] [Table 3]

[0160] [Table 4]

[0161] These supporting data indicate that the pharmaceutical composition is stable for a minimum of six months (until the end of the study). No adverse trends were identified under long-term or accelerated conditions. Quantitative results were consistent throughout the study and no new related species were observed during the stability study. Reporting of stability results for lots stored in a blister pack configuration is considered to support the updated packaging configuration of a 30mL HDPE bottle, induction seal, and child resistant cap. Both configurations are excipient-free and protected from light.

[0162] Example 3: Phase 1 Clinical Trial Compound 1 was investigated in healthy adult volunteers in two Phase 1 studies.

[0163] Study 1 was a first-in-human study that investigated the safety, tolerability, and PK of single ascending doses of compound 1 administered orally to healthy adult subjects. Safety and tolerability were evaluated across a wide range of single oral doses, and dose escalation was undertaken after review of safety data from the previous dose. Data from this study were used to guide dose selection for study 2.

[0164] Study 2, a two-part, multiple-dose study, determined the safety and tolerability of repeated daily doses of Compound 1 and examined effects on biomarkers relevant to the treatment of alcohol dependence. Part B examined the interaction of Compound 1 with midazolam, a substrate of cytochrome P450 3A4 [CYP3A4], to determine whether Compound 1 significantly inhibits the metabolism of drugs metabolized by CYP3A4.

[0165] In the first study, Compound 1 was administered as a single oral dose of 2, 10, 50, 150, 400, or 800 mg to healthy adult subjects in the fed state, and as a single oral dose of 150 mg to healthy adult subjects in the fasted state. In the fed state, absorption occurred somewhat slower, with C max We've reached the peak.

[0166] Table 5 summarizes the PK parameters at each dose level. When Compound 1 was administered under fed conditions, the time to maximum plasma concentration (T max ) occurred between 4 and 6 hours. When 150 mg of Compound 1 was administered in the fasting state, T max The median half-life (t) after a single oral dose was 10.05 hours, ranging from 6 to 12 hours, suggesting that delayed absorption may occur under fasting conditions. 1 / 2 ) (fed and fasted) was 31 to 44 h, with a range of 11 to 101 h. The apparent volume of distribution (V z / F) was large and varied considerably, with the greatest variability seen at the top two dose levels, 400 mg and 800 mg.

[0167] [Table 5]

[0168] As part of this single-dose ascending study, the effect of food on PK was investigated, examining exposure to the 150 mg dose level of Compound 1 in both fed and fasted states. A total of six subjects received 150 mg of Compound 1 in each of these two dose groups. Of these six subjects, four subjects received the same dose of Compound 1 in both fed and fasted states. Compound 1 administration in the fasted state produced a significantly flatter mean concentration-time (i.e., significantly less absorption) profile when compared to the mean profile at the same dose obtained within 5 minutes after a standardized breakfast. AUC for the 150 mg dose in the fed state 0-∞ and C max The mean values ​​of were approximately 3-fold and 11-fold greater than those in the fasted state, respectively. Table 6 summarizes the PK parameters at the 150 mg dose level under both fed and fasted conditions.

[0169] [Table 6]

[0170] Dose proportionality of Compound 1 at doses of 50 to 800 mg administered under fed conditions, as measured by the PK parameter AUC 0-∞ and C max The results of this analysis showed that with each doubling of dose, the AUC 0-∞ It was suggested that the increase in β-amyloides was predicted to be 1.74-fold higher than predicted based on dose proportionality. max The dose-proportionality curve for the various doses administered in the fed state was not consistent with the AUC 0-∞ or C max No conclusions could be drawn from this.

[0171] PK was also evaluated in Study 2, a multiple-ascending dose study. In Part A of the study, subjects were divided into three cohorts and administered 50 mg, 150 mg, or 200 mg of Compound 1 or placebo for 14 consecutive days (at least six subjects in each cohort received Compound 1 and two subjects received placebo). Compound 1 blood concentrations were close to steady-state values ​​two weeks after dosing, with accumulation ratios ranging from 2.51 to 3.65. In Part B, the interaction of Compound 1 with midazolam (a substrate for CYP3 A4) was examined to determine whether this compound significantly inhibits the metabolism of drugs metabolized by CYP3 A4. Serial blood samples were collected to determine plasma concentrations of the test drug after a single dose of Compound 1 and at steady state. All doses were administered relative to the fed state. Assessment of diurnal cortisol levels was performed both before and during the dosing period, as well as under glucose clamp conditions.

[0172] Overall, the concentration-time profile of Compound 1 indicated that absorption was rather slow, with C max Consistent with the single-dose study (Study 1) described above, concentrations appeared to decline biexponentially, characterized by a rapid decline during the first 24 hours. After 2 weeks of multiple daily dosing, the t 1 / 2 That is, the accumulation ratio of compound 1 was 2.51 to 3.65 (see Table 7). max appeared to be consistent across doses. Overall, half-life, weight-normalized CL / F, and V / F were consistent between 150 and 200 mg; however, values ​​for the latter two parameters nearly doubled at the 50 mg dose level. Variability (CV%) in apparent clearance and volume of distribution was large but not reduced by weight normalization.

[0173] [Table 7-1]

[0174] [Table 7-2]

[0175] Table 8 shows the AUC 0-24 and C max The results of the dose proportionality evaluation for AUC 0-24 and C max For all of the adjusted means of slopes on days 1 and 14, the AUC 0-24 and C max This shows that the increase in the value of is slightly more than proportional.

[0176] [Table 8] safety

[0177] Two Phase 1 studies (Study 1 and Study 2) evaluated the safety of Compound 1 in healthy adult volunteers. Both studies assessed adverse events (AEs), clinical laboratory tests, vital signs (supine blood pressure and pulse rate), and electrocardiograms (ECGs). Overall, Compound 1 was well tolerated in Study 1.

[0178] Compound 1 was generally well tolerated in the healthy population tested at multiple doses up to 200 mg. The first study examined effects on biomarkers relevant to the treatment of alcohol dependence. The effects of Compound 1 were compared against placebo using five clusters of the ARCI-49 (Addiction Research Center Inventory Questionnaire): the Morphine-Benzedrine Group Scale, a measure of euphoria; the Acid-Diethylamide Group Scale, assessing dysphoria and physical changes; the Pentobarbital-Chlorpromazine-Alcohol Group Scale, a measure of sedation; the Benzedrine Group (BG), a measure of intellectual efficiency and energy; and the Amphetamine Group Scale, a measure of the effects of d-amphetamine. No systematic patterns or dose-responses were identified in the changes from baseline or differences above placebo within each cluster.

[0179] In summary, single oral doses of up to 800 mg and multiple doses of up to 200 mg of Compound 1 were well tolerated in healthy male and female subjects.

[0180] Example 4: Phase 2 Clinical Trial Cohort A of the Phase 2 study will involve a 6-week, multiple-ascending dose study of Compound 1 for the treatment of adult patients with classical CAH. After screening, eligible patients will be enrolled in a 6-week treatment period followed by a 4-week washout / safety follow-up period.

[0181] This cohort will consist of approximately nine patients, who will receive Compound 1 daily for up to six weeks. Compound 1 will be administered as an oral daily dose. Patients will be titrated with Compound 1 at two-week intervals through three ascending dose strengths. Patients will undergo overnight PK / PD assessments at baseline, including a pre-dose overnight PK / PD assessment and a post-dose overnight PK / PD assessment after administration of the first dose. At the end of each two-week dosing period, patients will return for one overnight visit for steady-state PK / PD assessment. Outpatient visits during the follow-up period will occur 30 days after the last dose. After completion of the first cohort (Cohort A), the study will progress to a multiple ascending dose (MAD) design with up to three successive cohorts (Cohort B, Cohort C, and Cohort D) to further evaluate the safety, PK, and PD of various SPR001 dosing regimens and identify optimal dosing. Each cohort will undergo a 2-week run-in period, a 2-week treatment period, and a 30-day washout and safety follow-up period. The run-in period will be conducted at screening, during which subjects will complete a paper diary of each dose of glucocorticoid medication taken, the times of each meal, and daily bedtime and wake-up times to ensure compliance with the background glucocorticoid regimen and stability of the subjects' daily routine.

[0182] Patients in Cohort B will receive 200 mg of study drug twice daily, once in the morning and once in the evening, with consumption of the drug with meals or a unified snack. For Cohorts C and D, dose levels, frequency, and timing will be determined based on interim data from the previous cohort. However, the dose level of each successive cohort will be up to twice the daily dose level of the previous cohort. Study design Type of study: Interventional study ·Main purpose: treatment Phase of study: Phase 2 Intervention trial model: sequential allocation Number of cohorts: Maximum 4 Shielding: No shielding Allocation: Non-randomized - Enrollment: Maximum 27 people (estimated)

[0183] [Table 9] Evaluation items Primary endpoint: 1.Evaluation of the safety of Compound 1 in subjects with CAH 2. Evaluate the safety of Compound 1 in subjects with classical CAH, as measured by percent and absolute change in 17-OHP compared to baseline Secondary endpoints: 3. Find the dose of Compound 1 that produces pharmacodynamic changes in plasma concentrations of ACTH, androstenedione, and testosterone, as measured by absolute and percent change from baseline with treatment. 4. Confirmation of the pharmacokinetics of Compound 1 in subjects with CAH 5. Exploring possible relationships between pharmacology and pharmacokinetics Examination 6. Identify doses of Compound 1 that induce changes in urinary pharmacodynamic biomarkers, as measured by absolute and percent change from baseline with treatment Eligibility Minimum age: 18 years Maximum age: Gender: Both men and women Gender consideration: None Healthy volunteers: None Criteria: Inclusion on the boundary standard: Selection criteria: ·Male and female patients aged 18 years or older. · A documented diagnosis of classic CAH due to 21-hydroxylase deficiency -17-OHP is elevated at screening -Continued stable glucocorticoid replacement therapy for at least 30 days Exclusion criteria: · Clinically significant unstable medical condition, illness, or chronic disease Clinically significant psychiatric disorder Clinically significant abnormalities in laboratory findings or evaluations History of bilateral adrenalectomy or hypopituitarism Pregnant or nursing women Use of any other investigational drug within 30 days Inability to understand and comply with study procedures, inability to understand the risks, and / or unwillingness to provide written informed consent result: This Phase 2 study demonstrated that Compound 1 was generally well tolerated. The study explored a broad dose range (5-fold range) before establishing a range of safe doses (see Figure 1).

[0184] Regarding patient-level response to Compound 1, 80% showed a decrease in ACTH (see Figure 2). Attenuation of ACTH is usually indicative of target engagement and functional CRF1 receptor antagonism. 80% of patient subjects showed a decrease in ACTH. 70% of subjects showed a decrease in ACTH of more than 25%. 40% of subjects were in the normal range after treatment.

[0185] Based on standard endpoint criteria, a decrease in 17-OHP indicates "control" of the disease. This allows steroids to be tapered. 80% of subjects showed a decrease in 17-OHP (see Figure 3). 50% of subjects showed a >25% decrease in 17-OHP. 50% of subjects were within reference range (1200 ng / dL) after treatment.

[0186] Compound 1 attenuated the morning increase in A4, indicating that Compound 1 can control excess androgen production and associated symptoms (see Figure 4). 100% of subjects showed a reduction in androstenedione (at various doses). 60% of subjects showed a reduction in androstenedione of more than 25%. 50% of subjects were within the normal reference range after treatment.

[0187] Example 5: Three-Month Phase 2 Study Here, a 3-month Phase 2 study will evaluate the safety and efficacy of Compound 1 in subjects with classical CAH. The study will investigate the long-term use of Compound 1 over a 3-month period in combination with glucocorticoid and mineralocorticoid replacement in the treatment of CAH.

[0188] The study will enroll up to 24 eligible subjects who will receive Compound 1 daily for up to 3 months. Compound 1 will be administered as a daily oral dose. At the end of each 2-week treatment period, patients will return for morning laboratory evaluations. Follow-up outpatient visits will occur 30 days after the last dose. Study design Type of study: Interventional study ·Main purpose: treatment Phase of study: Phase 2 Intervention trial model: sequential allocation Number of groups: 1 Shielding: No shielding Allocation: Non-randomized - Enrollment: Maximum 24 people (estimated) Evaluation items Primary endpoint: 1. Evaluate the safety of Compound 1 in subjects with CAH. Secondary endpoints: 2. Evaluating the safety of Compound 1 in subjects with CAH in terms of hormonal changes Examination: 3. Assessment of the impact of Compound 1 on quality of life, metabolic parameters, exploratory adrenal hormones, and semen analysis in subjects with CAH. Eligibility: Minimum age: 18 years Maximum age: Gender: Both men and women Gender consideration: None Healthy volunteers: None Criteria: Inclusion on the boundary standard: Selection criteria: ·Male and female patients aged 18 years or older. · A documented diagnosis of classic CAH due to 21-hydroxylase deficiency -17-OHP is elevated at screening -Continued stable glucocorticoid replacement therapy for at least 30 days Exclusion criteria: · Clinically significant unstable medical condition, illness, or chronic disease Clinically significant psychiatric disorder Clinically significant abnormalities in laboratory findings or evaluations History of bilateral adrenalectomy or hypopituitarism Pregnant or nursing women Use of any other investigational drug within 30 days Inability to understand and comply with study procedures, inability to understand the risks, and / or unwillingness to provide written informed consent

[0189] Example 6: Study in adolescent patients Here, we present a phase 2, open-label, multiple-dose study designed as a proof-of-concept study of the use of compound 1 to treat adolescent patients aged 12-17 years with classical CAH. The study will assess the safety, efficacy, and PK of 2 weeks of treatment with Compound 1. Each subject will complete a 2-week diary run-in period at screening, a 2-week treatment period, and a 30-day washout and safety follow-up period.

[0190] An adaptive design with up to three successive dose cohorts (Cohorts 1, 2, and 3) will be planned to identify optimal dose intensity and dosing schedule in adolescent patients with classical CAH. Each cohort will initially enroll three subjects and may subsequently enroll three more subjects for a total of six subjects per cohort based on interim data from the first three subjects. However, if safety, efficacy, and PK results from the six subjects are inconclusive, the cohort may be expanded to a maximum of 12 subjects. Cohort 1 will receive 200 mg of study drug daily. Cohorts 2 and 3 will be activated sequentially only if further investigation of optimal dose intensity or dosing schedule is required. For these cohorts, the dose intensity, dosing frequency, and dosing timing will be determined based on interim data from the previous cohorts. However, the dose intensity administered to each successive cohort will be up to twice the daily dose intensity administered to the previous cohort.

[0191] The study will enroll patients with CAH who are inadequately controlled with existing glucocorticoid (GC) therapy (including any currently available therapy: hydrocortisone, prednisone / prednisolone, and / or dexamethasone). In practice, typical treatment for CAH patients is with supraphysiological doses of GCs, which are toxic and ineffective in many adolescent patients. In this population, GCs are associated with multiple, well-described, short-term and long-term toxicities, including growth retardation, weight gain, hypertension, hyperglycemia, hyperlipidemia, and Cushingoid features.

[0192] The goal of treating this patient population with Compound 1 is to reduce (or normalize) key hormone-related endpoints, thereby reducing the need for GC supplementation and thus improving growth velocity and other clinical outcomes of concern. Improvement of hormone-related endpoints in this population would also be expected to delay precocious puberty and bone maturation, ultimately leading to improved height in adolescent patients with CAH. Evaluation items Primary endpoint: 1.Evaluate the safety of Compound 1 in adolescent subjects with CAH. Secondary endpoints: 2. Evaluate the dose of Compound 1 that induces changes in key pharmacodynamics biomarkers in blood in adolescent subjects with CAH. 3. Investigating the effect of Compound 1 on quality of life in adolescent subjects with CAH. 4. Confirmation of the pharmacokinetics of Compound 1 in adolescent subjects with CAH. 5. To investigate possible relationships between pharmacology and pharmacokinetics in adolescents with CAH. Examination 6. Identifying doses of Compound 1 that induce changes in exploratory pharmacodynamic biomarkers in blood and urine in adolescent subjects with CAH. Eligibility Criteria Selection criteria: · For men and women aged 12 to 17 · A documented diagnosis of classic CAH due to 21-hydroxylase deficiency -17-OHP is elevated at screening -Continued stable glucocorticoid replacement therapy for at least 30 days Exclusion criteria: · Clinically significant unstable medical condition, illness, or chronic disease Clinically significant psychiatric disorder Clinically significant abnormalities in laboratory findings or evaluations History of bilateral adrenalectomy or hypopituitarism Pregnant or nursing women Use of any other investigational drug within 30 days Inability to understand and comply with study procedures, inability to understand the risks, and / or unwillingness to provide written informed consent

[0193] Example 7: Phase 3 Clinical Trial This is a 24-week, randomized, double-blind, placebo-controlled study to treat classical CAH with Compound 1. After screening, eligible patients will be enrolled in a 24-week treatment period followed by a 4-week safety follow-up period.

[0194] Subjects included in the study will be randomized in a 1:1 ratio to receive Compound 1 or a matching placebo for up to 24 weeks. Compound 1 or placebo will be administered as a daily oral dose. Patients will return for study visits approximately monthly. Outpatient visits during follow-up will occur 30 days after the last dose. Initial plans are to enroll a maximum of approximately 150 patients.

[0195] Consistent with the Phase 2 trial design, Phase 3 clinical trials will seek to enroll patients with CAH who are inadequately controlled with existing glucocorticoid (GC) therapy (including any currently available therapy: hydrocortisone, prednisone / prednisolone, and / or dexamethasone). In practice, typical treatment for patients with CAH is with supraphysiological doses of GCs, which are toxic and ineffective in the majority of patients. GCs are associated with multiple, well-described, short-term and long-term toxicities in adults, including, for example, excess weight gain, hypertension, hyperglycemia, hyperlipidemia, and Cushingoid features. Study design: Type of study: Interventional study ·Main purpose: treatment Phase of study: Phase 3 Intervention trial model: Randomized controlled trial Allocation: Randomization Enrollment: 150 people (estimated) Evaluation items Primary endpoint 1. Evaluation of the efficacy of Compound 1 in reducing A4 and 17-OHP in patients with CAH. Secondary endpoints 2. Evaluation of the efficacy of Compound 1 in CAH patients in terms of changes in key hormones. 3. Assess the efficacy of Compound 1 in improving quality of life and / or mood in patients with CAH. 4. Evaluate the efficacy of Compound 1 in improving hyperandrogenism in patients with CAH. 5. Evaluation of the efficacy of Compound 1 in improving metabolic parameters in CAH patients. 6.Evaluation of the safety of Compound 1 in patients with CAH. Eligibility Minimum age: 16 years old Maximum age: Gender: Both men and women Gender consideration: None Healthy volunteers: None Criteria: Inclusion on the boundary standard Selection criteria: Male and female patients aged 16 years and older. · A documented diagnosis of classic CAH due to 21-hydroxylase deficiency Increase in 17-OHP -Continued stable glucocorticoid replacement therapy for at least 30 days Exclusion criteria: · Clinically significant unstable medical condition, illness, or chronic disease Clinically significant psychiatric disorder Clinically significant abnormalities in laboratory findings or evaluations History of bilateral adrenalectomy or hypopituitarism Pregnant or nursing women Use of any other investigational drug within 30 days Inability to understand and comply with study procedures, inability to understand the risks, and / or unwillingness to provide written informed consent

[0196] Example 8: Phase 3 Open-Label Extension (OLE) and Steroid-Sparing Study Following completion of the study described in Example 7, eligible patients will have the opportunity to be enrolled in an open-label extension study lasting up to one year. In this open-label study, all eligible patients will receive active study drug during their participation in the Phase 3 program. Patients will undergo study evaluations every 1-3 months during this open-label phase and will be evaluated for long-term safety and efficacy (including both hormone-related endpoints and long-term clinical outcome measures of concern in this population).

[0197] Further trials may seek to enroll CAH patients who are inadequately controlled with existing glucocorticoid (GC) therapy (including any currently available therapy: hydrocortisone, prednisone / prednisolone, and / or dexamethasone). Typical treatment for such CAH patients is with supraphysiological doses of GCs, which are toxic and ineffective in the majority of patients. GCs are associated with multiple, well-described, short-term and long-term toxicities in adults, including, for example, excessive weight gain, hypertension, hyperglycemia, hyperlipidemia, and Cushingoid features.

[0198] After a treatment period during which the GC dose is kept stable (e.g., 12 weeks), patients in this study will have the GC dose tapered from a supraphysiological dose to a lower dose that is equivalent to or close to the physiologic dose of the GC.

[0199] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will immediately occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims

1. Use of a corticotropin releasing factor-1 (CRF1) receptor antagonist, or a pharma- tically acceptable salt thereof, in the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH), said treatment comprising administering to a subject in need thereof a therapeutically effective amount of a small molecule CRF1 receptor antagonist, or a pharma- tically acceptable salt thereof; the small molecule CRF 1 receptor antagonist is administered at a dose of about 50 mg / day to about 800 mg / day; The administering reduces obesity, insulin resistance, metabolic disorders, hypertension, cardiovascular disease or osteoporosis, or a combination thereof.

2. The use of claim 1, wherein the administering reduces hormone levels, and the hormones include deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, aldosterone, pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone (17-OHP), dehydroepiandrosterone, androstenediol, androstenedione (A4), testosterone, dihydrotestosterone, estrone, estradiol, estriol or adrenocorticotropic hormone (ACTH), or combinations thereof.

3. The use of claim 1, wherein the administering reduces hormone levels, and the hormone comprises 17α-hydroxyprogesterone (17-OHP), androstenedione (A4) or adrenocorticotropic hormone (ACTH), or a combination thereof.

4. The use described in claim 2 or 3, wherein the hormone levels in the subject are reduced by at least 20% from baseline.

5. The use described in claim 2 or 3, wherein the hormone levels in the subject are reduced by at least 30% from baseline.

6. The use of claim 4 or 5, wherein the baseline comprises an overnight assessment prior to administration of the small molecule CRF1 receptor antagonist and an overnight assessment after administration of a first dose of the small molecule CRF1 receptor antagonist.

7. The use of any one of claims 1 to 6, wherein the small molecule CRF 1 receptor antagonist, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 50 mg / day.

8. The use of any one of claims 1 to 6, wherein the small molecule CRF 1 receptor antagonist, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 100 mg / day.

9. The use of any one of claims 1 to 6, wherein the small molecule CRF 1 receptor antagonist, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 200 mg / day.

10. The use of any one of claims 1 to 9, wherein the small molecule CRF 1 receptor antagonist is administered orally.

11. The use of any one of claims 1 to 10, wherein the small molecule CRF 1 receptor antagonist is administered twice daily.

12. The use of any one of claims 1 to 11, wherein the small molecule CRF 1 receptor antagonist is administered for at least 14 consecutive days.

13. The use of claim 12, wherein the subject is administered the small molecule CRF 1 receptor antagonist in a fed state for each of 14 consecutive days.

14. The small molecule CRF 1 receptor antagonist comprising: 【Chemistry 1】 14. The use according to any one of claims 1 to 13, wherein the compound is (Compound 1) or a pharma- ceutically acceptable salt thereof.

15. The use described in any one of claims 1 to 14, wherein the treatment further comprises administering a glucocorticoid.

16. The use of claim 15, wherein the glucocorticoid is selected from beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone, or a combination thereof.

17. The use described in claim 16, wherein the glucocorticoid is hydrocortisone.

18. The use described in any one of claims 1 to 17, wherein the CAH is classical CAH.

19. The use described in any one of claims 1 to 18, wherein the subject is at least 12 years of age.

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