Crf1 receptor antagonist, and pharmaceutical formulations and solid forms thereof, for treatment of congenital adrenal hyperplasia

Abstract

To provide methods related to treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Formula I), or a pharmaceutically acceptable salt thereof.SOLUTION: Further provided are pharmaceutical formulations and solid forms of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, and their use in treatment of congenital adrenal hyperplasia (CAH).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for treating congenital adrenal hyperplasia (CAH). The present disclosure further relates to pharmaceutical formulations and solid forms of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, and their uses in the treatment of congenital adrenal hyperplasia (CAH). [Background technology]

[0002] Classical congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by 21-hydroxylase deficiency, an enzyme that alters the production of adrenal steroids, resulting in little or no cortisol biosynthesis. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels lead to adrenal hyperplasia, and enzyme mutations trigger a switch to an alternative pathway for cortisol precursor steroids. Most notably, androgen switching leads to virilization and other developmental complications in females, while excessive ACTH accumulation is associated with the formation of testicular adrenal resting tumors in males. Furthermore, because the same enzyme (21-hydroxylase) is used in the pathway for mineralocorticoid biosynthesis, some such patients suffer from aldosterone deficiency, which can lead to salt-wasting dehydration and death. In the general US population, the prevalence of classic 21-hydroxylase deficiency CAH, based on newborn screening, has been documented to be 1:10,000–1:20,800 (Trakakis et al., “An update to 21-hydroxylase deficient congenital adrenal hyperplasia,” Gynecol. Endocrinol. (2010) 26(1):63–71; Hertzberg et al., “Birth prevalence rates of newborn screening disorders in relation to screening practices in the United States,” J. Pediatr. (2011) 159(4):555-560).

[0003] Pediatric patients, from birth through adolescence, and women in particular appear to be the most vulnerable populations of CAH sufferers, representing the patient subgroup with the greatest unmet medical needs (Cheng and Speiser, "Treatment outcomes in congenital adrenal hyperplasia," Adv. Pediatr. (2012) 59(1):269-281; ​​Merke and Poppas, "Management of adolescents with congenital adrenal hyperplasia," Lancet Diabetes Endocrinol. (2013) 1(4):341-352). Excessive androgen production in these young patients leads to precocious puberty and adrenarche, altered skeletal maturation patterns, growth retardation caused by premature growth plate fusion, and significant hirsutism and acne problems. Survival is adequately ensured by steroid replacement strategies based on physiological dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone). However, these doses are often inadequate to suppress ACTH accumulation and the overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). Uncontrolled symptoms of androgen excess can significantly impact the daily function and development of these patients.

[0004] Currently, exogenous corticosteroids are the standard of care for treating patients with classic CAH. This treatment corrects cortisol deficiency and reduces excessive ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH is usually significantly higher than the normal physiological levels used with cortisol replacement alone (as in patients with Addison's disease). Increased exposure to glucocorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth rate, and decreased bone mineral density in CAH patients (Elnecave et al., "Bone mineral density in girls"). with classical congenital adrenal hyperplasia due to CYP21 deficiency,” J. Pediatr. Endocrinol. Metab. (2008) 21(12):1155-1162; King et al., “Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia,” J. Clin. Endocrinol. Metab. (2006) 91(3):865-869; Migeon and Wisniewski, “Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations,” Endocrinol. Metab. Clin. North Am. (2001) 30(1):193-206). Corticotropin-releasing factor (CRF) is a hypothalamic hormone released directly into the pituitary portal vasculature, where it acts on specific corticotropin-releasing factor 1 (CRF1) receptors on the surface of corticotropin-secreting cells in the anterior pituitary gland to stimulate ACTH release. Blocking these receptors has been shown to reduce ACTH release in both animals and humans. Therefore, compounds that block the CRF1 receptor have the potential to directly inhibit the excessive ACTH release that occurs in CAH, thereby allowing for normalization of androgen production while requiring less physiologically high doses of hydrocortisone. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Trakakis et al., “An update to 21-hydroxylase deficient congenital adrenal hyperplasia,” Gynecol. Endocrinol. (2010) 26(1):63-71 [Non-patent document 2] Hertzberg et al., “Birth prevalence rates of newborn screening disorders in relation to screening practices in the United States,” J. Pediatr. (2011) 159(4):555-560 [Non-patent document 3] Cheng and Speiser, “Treatment outcomes in congenital adrenal hyperplasia,” Adv. Pediatr. (2012) 59(1):269-281 [Non-patent document 4] Merke and Poppas, “Management of adolescents with congenital adrenal hyperplasia,” Lancet Diabetes Endocrinol. (2013) 1(4):341-352 [Non-patent document 5] Elnecave et al., “Bone mineral density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency,” J. Pediatr. Endocrinol. Metab. (2008) 21(12):1155-1162 [Non-patent document 6] King et al., “Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia,” J. Clin. Endocrinol. Metab. (2006) 91(3):865-869 [Non-Patent Document 7] Migeon and Wisniewski, “Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations,” Endocrinol. Metab. Clin. North Am. (2001) 30(1):193-206 Summary of the Invention [Means for solving the problem]

[0006] The compound of formula (I), 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine [ka] is a selective CRF1 receptor antagonist. The compound of formula (I) can be prepared according to the methods described in U.S. Patent Nos. 6,586,456 and 8,314,249, each of which is incorporated herein by reference in its entirety. The compound of formula (I) is a low-solubility compound with low bioavailability. Due in part to its low solubility, attempts to formulate the compound of formula (I) have proven difficult, particularly to formulate it in a manner suitable for pediatric administration.

[0007] Thus, there is a need for a treatment for CAH that avoids the serious complications associated with corticosteroid therapy. There is also a need for formulations of the compound of formula (I) that have improved bioavailability, as well as a need for formulations of the compound of formula (I) that are suitable for pediatric administration. The formulations and methods of the present invention help address these and other needs.

[0008] (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and (b) one or more of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer Provided herein is a pharmaceutical composition comprising:

[0009] (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (b) one or more of a sweetener, an antioxidant, and a flavoring agent; and (c) Liquid vehicle Provided herein is a pharmaceutical composition in oral solution dosage form comprising:

[0010] Also provided herein are pharmaceutical compositions of the present disclosure (e.g., pharmaceutical compositions in oral solution dosage form of the present disclosure) for use in therapy, e.g., for use in any of the methods disclosed herein.

[0011] A method for treating congenital adrenal hyperplasia (CAH), comprising administering to a patient of formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0012] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of treating congenital adrenal hyperplasia in a subject.

[0013] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia in a subject.

[0014] Provided herein is a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in the subject.

[0015] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of treating congenital adrenal hyperplasia in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in the subject.

[0016] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in the subject.

[0017] In some embodiments, a decrease in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during circadian release on a day before administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof with the level of the biomarker measured during circadian release on a day after administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. In some embodiments, circadian release occurs between 2:00 AM and 10:00 AM.

[0018] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered 3 to 8 hours prior to the circadian release of the biomarker.

[0019] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 25%. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 50%.

[0020] In some embodiments, adrenocorticotropic hormone levels are reduced by at least 25%. In some embodiments, adrenocorticotropic hormone levels are reduced by at least 40%. In some embodiments, adrenocorticotropic hormone levels are reduced by at least 50%.

[0021] In some embodiments, androstenedione levels are reduced by at least 25%. In some embodiments, androstenedione levels are reduced by at least 30%. In some embodiments, androstenedione levels are reduced by at least 50%.

[0022] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 50% and the level of androstenedione is reduced by at least 50%.

[0023] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base.

[0024] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form.

[0025] Provided herein is a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne and growth dysfunction in a subject with classic congenital adrenal hyperplasia, comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce androstenedione level.In some embodiments, the growth dysfunction is selected from one or more of: accelerated height growth rate, accelerated weight gain rate or accelerated bone age.

[0026] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth dysfunction in a subject with classic congenital adrenal hyperplasia, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce androstenedione levels in the subject.

[0027] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth dysfunction in a subject with classic congenital adrenal hyperplasia, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce androstenedione levels in the subject.

[0028] In some embodiments, androstenedione levels are reduced by at least 25%. In some embodiments, androstenedione levels are reduced by at least 30%. In some embodiments, androstenedione levels are reduced by at least 50%.

[0029] Provided herein is a method for reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia, the method comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof.

[0030] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia.

[0031] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia.

[0032] In some embodiments, the one or more biomarkers of congenital adrenal hyperplasia are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0033] Provided herein is a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia to manage the condition, comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is a glucocorticoid.

[0034] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia.

[0035] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia.

[0036] 1. A method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising the step of administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, or the like. , growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection.

[0037] 1. A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method for reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, wherein the side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal depression, or the like. Provided herein is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: inflammatory bowel disease, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection.

[0038] 1. Use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, wherein the side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushing's syndrome, steroid hormone receptor agonist (SHR), ... Provided herein is a use wherein the side effects are selected from: inflammatory bowel disease, ...

[0039] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% compared to pre-administration levels.

[0040] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce androstenedione levels by at least 30% compared to pre-administration levels.

[0041] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to (a) reduce 17-hydroxyprogesterone (17-OHP) levels by at least 50% compared to pre-administration levels, and (b) reduce androstenedione levels by at least 30% compared to pre-administration levels.

[0042] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base.

[0043] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base.

[0044] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form.

[0045] 1. A method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have an elevated level of one or more biomarkers, administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. A method is provided herein, comprising:

[0046] Similarly, there is provided a method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have an elevated level of one or more biomarkers, administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof, for use in a method comprising:

[0047] Similarly, there is provided the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia in a subject, said method comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have an elevated level of one or more biomarkers, administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. Uses are provided herein, including

[0048] In some embodiments, the method further comprises (iv) measuring the level of one or more biomarkers in a biological sample obtained from the subject after administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof to determine whether the subject has a decreased level of the one or more biomarkers compared to the measurements in step (i). In some embodiments, the method further comprises (v) continuing to administer 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof if the subject has a decreased level of the one or more biomarkers.

[0049] In some embodiments, steps (i) and (iv) are performed in a similar manner and on biological samples collected from a subject during the same time period of a day. In some embodiments, steps (i) and (iv) are performed on biological samples collected from a subject during a time period of a day between 2:00 AM and 10:00 AM. In some embodiments, steps (i) and (iv) are performed on biological samples collected from a subject during a time period of a day between 6:00 AM and 10:00 AM.

[0050] In some embodiments, steps (i) and (iv) comprise measuring the levels of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0051] In some embodiments, steps (i) and (iv) comprise measuring levels of (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0052] In some embodiments, step (i) includes measuring the level of 17-hydroxyprogesterone (17-OHP), and the level of 17-hydroxyprogesterone (17-OHP) is elevated if it is greater than or equal to 1,000 ng / dL.

[0053] In some embodiments, step (i) comprises measuring the level of androstenedione, wherein the level of androstenedione is elevated if it is greater than 200 ng / dL.

[0054] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form.

[0055] Provided herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state.

[0056] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject, wherein the subject is in a fed state.

[0057] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject, wherein the subject is in a fed state.

[0058] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or its pharmaceutically acceptable salt is administered to a subject together with a nutritional composition.In some embodiments, the nutritional composition is a liquid dietary supplement containing about 1500 calories per liter, with a calorie distribution of about 14.7% protein, about 32% fat and about 53.3% carbohydrate.In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or its pharmaceutically acceptable salt is administered to a subject together with a nutritional composition.In some embodiments, the nutritional composition is a liquid dietary supplement containing 1500 calories per liter, with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrate.In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof exhibits a positive food effect. In some embodiments, the positive food effect is a C when comparing oral administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in the fed and fasted states. max , AUC or a combination thereof.

[0061] In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is about 5 to about 10. max C in the fasting state max The ratio to is about 5 to about 10.

[0062] Provided herein is a method for reducing the glucocorticoid load in a subject as measured after a period of administration of a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, wherein the reduction in glucocorticoid load is relative to the glucocorticoid load prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0063] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing glucocorticoid load in a subject, wherein the reduction in glucocorticoid load is relative to the glucocorticoid load before administering the compound or a pharmaceutically acceptable salt thereof.

[0064] Also provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of reducing glucocorticoid load in a subject, wherein the reduction in glucocorticoid load is relative to the glucocorticoid load before administering the compound or a pharmaceutically acceptable salt thereof.

[0065] Provided herein is a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, testicular adrenal rest tumor control, and fertility in a subject with classic congenital adrenal hyperplasia, comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the symptoms improve after a period of administration of the compound or a pharmaceutically acceptable salt thereof, and the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0066] Provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility in a subject with classic congenital adrenal hyperplasia, wherein the symptoms improve after a period of administration of the compound or a pharmaceutically acceptable salt thereof, and the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0067] Provided herein is the use of a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility in a subject with classic congenital adrenal hyperplasia, wherein the symptoms improve after a period of administration of the compound or a pharmaceutically acceptable salt thereof, and the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0068] Also provided herein is a compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in therapy, for example, for use in any of the methods disclosed herein.

[0069] Similarly, there is provided herein the use of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any of the methods disclosed herein.

[0070] Similarly, the following formula (I): [ka] Provided herein is a spray-dried dispersion comprising 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine having the formula: or a pharmaceutically acceptable salt thereof, and a polymer. In some embodiments, the polymer is selected from a neutral polymer, an enteric polymer, and a pyrrolidone polymer. In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is about 1:9 to about 1:1.

[0071] In some embodiments, the polymer is a neutral polymer. In some embodiments, the neutral polymer is selected from hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC).

[0072] In some embodiments, the polymer is an enteric polymer, hi some embodiments, the enteric polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), amino methacrylate copolymers, ammonioalkyl methacrylate copolymers, and methacrylic copolymers.

[0073] In some embodiments, the polymer is a pyrrolidone polymer. In some embodiments, the pyrrolidone polymer is selected from polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone vinyl acetate (PVP / VA). In some embodiments, the pyrrolidone polymer is PVP / VA. In some embodiments, the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 40:60 to about 60:40. In some embodiments, the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 60:40. In some embodiments, the copolymer has the following structure: [ka] where the value of n is about 1 to about 2 times the value of m. In some embodiments, the copolymer is copovidone, where the value of n is about 1.16 times the value of m. In some embodiments, the copolymer is copovidone having an average molecular weight of about 45,000 to about 70,000.

[0074] 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, having the following formula (I): [ka] or a pharmaceutically acceptable salt thereof, and a polymer which is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the following structure: [ka] wherein the value of n is about 1 to about 2 times the value of m, and the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 60:40, wherein the weight ratio of the compound of Formula (I) to the copolymer is about 1:1 to about 1:9.

[0075] In some embodiments of the spray-dried dispersions of the present disclosure, the compound of formula (I) and the polymer together form uniform particles. In some embodiments, the particles have a particle size distribution D of about 5 μm to about 100 μm. 50 In some embodiments, the particles have a particle size distribution D of about 10 μm to about 50 μm. 50 In some embodiments, the particles have a particle size distribution D of about 15 μm to about 30 μm. 50 It has.

[0076] In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is about 1:1.5 to about 1:9. In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is about 1:2.5 to about 1:4. In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is about 1:3.

[0077] In some embodiments, the particles have a residual solvent content of less than about 2% by weight. In some embodiments, the particles have a residual solvent content of less than about 1% by weight. In some embodiments, the particles have a residual solvent content of about 0.5% by weight or less.

[0078] In some embodiments, the compound of Formula (I) in the dispersion is substantially amorphous.

[0079] Similarly, provided herein is a method of preparing a spray-dried dispersion of the present disclosure, comprising dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a polymer in an organic solvent to form a solution, and spray-drying the solution to produce a spray-dried dispersion, wherein spray-drying forms uniform particles of the compound of formula (I) and the polymer.

[0080] In some embodiments, the method includes removing the organic solvent by drying the spray-dried dispersion after formation of the spray-dried dispersion. In some embodiments, the spray-dried dispersion is dried using a convection tray dryer. In some embodiments, the organic solvent is acetone.

[0081] In some embodiments, the spray dryer inlet temperature is about 60° C. to about 80° C. In some embodiments, the spray dryer inlet temperature is about 72° C.

[0082] In some embodiments, the spray dryer outlet temperature is from about 25° C. to about 45° C. In some embodiments, the spray dryer outlet temperature is about 35° C.

[0083] In some embodiments, the uniform particles comprise a bulk density of less than about 0.2 g / mL. In some embodiments, the uniform particles comprise a bulk density of less than about 0.15 g / mL.

[0084] In some embodiments, the uniform particles comprise a tap density of less than about 0.3 g / mL. In some embodiments, the uniform particles comprise a tap density of less than about 0.25 g / mL.

[0085] Also provided herein are pharmaceutical compositions comprising the spray-dried dispersion of the present disclosure and one or more pharmaceutically acceptable excipients. In some embodiments, the spray-dried dispersion is present in an amount of about 20% to about 90% w / w of the composition. In some embodiments, the spray-dried dispersion is present in an amount of about 40% to 80% w / w of the composition.

[0086] In some embodiments, the pharmaceutical excipient is selected from the group consisting of a filler, a lubricant, and combinations thereof. In some embodiments, the filler is selected from the group consisting of a binder, a diluent, a disintegrant, a glidant, a surfactant, and combinations thereof.

[0087] In some embodiments, the pharmaceutical composition is formulated in a unit dosage form, and the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 200 mg. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 75 mg to about 150 mg. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 50 mg. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 100 mg.

[0088] In some embodiments, the pharmaceutical composition is formulated as a tablet, capsule, sachet, powder, granule, coated particle, coated tablet, enteric coated tablet, enteric coated capsule, melt strip, or melt film. In some embodiments, the pharmaceutical composition is in tablet form. In some embodiments, the pharmaceutical composition is in capsule form. In some embodiments, the pharmaceutical composition is coated.

[0089] In some embodiments, the spray-dried dispersion is formulated for oral administration and exhibits a positive food effect when administered orally. In some embodiments, the spray-dried dispersion has a ratio of AUC in the fed state to AUC in the fasted state of about 5 to about 10. In some embodiments, the spray-dried dispersion has a C in the fed state of about 5 to about 10. max C in the fasting state max has a ratio to

[0090] Also provided herein is a method of preparing a pharmaceutical composition comprising combining a spray-dried dispersion of the present disclosure with one or more pharmaceutically acceptable excipients.

[0091] Also provided herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure.

[0092] Also provided herein is a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject.

[0093] Also provided herein is the use of a spray-dried dispersion of the present disclosure in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject.

[0094] In some embodiments, the spray-dried dispersion or pharmaceutical composition is administered to a fed subject. In some embodiments, the spray-dried dispersion or pharmaceutical composition is administered to a subject along with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement containing about 1,000 to about 2,000 calories per liter with a fat content greater than 30%. In some embodiments, the nutritional composition is a liquid dietary supplement containing 1,500 calories per liter with a calorie distribution of 14.7% protein, 32% fat, and 53.3% carbohydrate. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the spray-dried dispersion or pharmaceutical composition.

[0095] In some embodiments, administration of the spray-dried dispersion or pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is determined by a C when comparing oral administration of the spray-dried dispersion or pharmaceutical composition in the fed and fasted states. max In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is about 5 to about 10. In some embodiments, the C in the fed state is measured in terms of AUC, AUC, or a combination thereof. max C in the fasting state max In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is about 5 to about 10. In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is about 10 to about 20. max C in the fasting state max The ratio to is about 10 to about 20.

[0096] In some embodiments of the disclosed methods, the subject is a pediatric subject.

[0097] Also provided herein is a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure for use in therapy, e.g., for use in any of the methods disclosed herein.

[0098] Also provided herein is the use of a spray-dried dispersion of the present disclosure for the manufacture of a medicament for use in any of the methods disclosed herein.

[0099] Also provided herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0100] Also provided herein is a pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject.

[0101] Also provided herein is the use of a pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject.

[0102] Also provided herein are pharmaceutical compositions of the present disclosure comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, e.g., for use in any of the methods disclosed herein.

[0103] Also provided herein is the use of a pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any of the methods disclosed herein.

[0104] Similarly provided herein is a method for improving gastrointestinal absorption of a compound of formula (I) in a subject, comprising orally administering to the subject a therapeutically effective amount of a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0105] Also provided herein is a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure for use in a method for improving gastrointestinal absorption of a compound of formula (I) in a subject, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0106] Also provided herein is the use of a spray-dried dispersion of the present disclosure in the manufacture of a medicament for use in a method for improving gastrointestinal absorption of a compound of formula (I) in a subject, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0107] In some embodiments, the subject is a pediatric subject.

[0108] Similarly, provided herein is a method for improving the oral bioavailability of a compound of formula (I) in a subject, comprising orally administering to the subject a therapeutically effective amount of a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0109] Also provided herein is a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising a spray-dried dispersion of the present disclosure for use in a method of improving the oral bioavailability of a compound of formula (I) in a subject, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0110] Also provided herein is the use of a spray-dried dispersion of the present disclosure in the manufacture of a medicament for use in a method of improving the oral bioavailability of a compound of formula (I) in a subject, wherein the improvement is relative to oral administration of a compound of formula (I) that is not prepared as a spray-dried dispersion.

[0111] In some embodiments, the subject is a pediatric subject.

[0112] Similarly, provided herein is a crystalline salt which is the p-toluenesulfonate salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine.

[0113] Also provided herein is a crystalline salt that is the p-toluenesulfonate salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine for use in therapy, for example, for use in any of the methods disclosed herein.

[0114] Similarly, there is provided herein the use of a crystalline salt that is p-toluenesulfonate salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine for the manufacture of a medicament for use in any of the methods disclosed herein.

[0115] Other features and advantages of the methods, processes, formulations, and uses provided herein will become apparent from the following detailed description and figures, and from the claims. In an embodiment of the present invention, for example, the following items are provided: (Item 1) (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and (b) one or more of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer A pharmaceutical composition comprising: (Item 2) 2. The pharmaceutical composition according to item 1, comprising about 1% by weight to about 20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 3) 2. The pharmaceutical composition according to item 1, comprising about 5% to about 15% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 4) Item 1. The pharmaceutical composition according to item 1, comprising about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 5) 5. The pharmaceutical composition according to any one of items 1 to 4, comprising an oil phase vehicle. (Item 6) 6. The pharmaceutical composition according to any one of items 1 to 5, comprising about 1% to about 50% by weight of said oil phase vehicle. (Item 7) 6. The pharmaceutical composition according to any one of items 1 to 5, comprising about 20% to about 50% by weight of said oil phase vehicle. (Item 8) 6. The pharmaceutical composition according to any one of items 1 to 5, comprising about 35% to about 45% by weight of said oil phase vehicle. (Item 9) 6. The pharmaceutical composition according to any one of items 1 to 5, comprising about 39% by weight of said oil phase vehicle. (Item 10) 10. The pharmaceutical composition according to any one of items 1 to 9, wherein the oil phase vehicle is selected from medium chain triglycerides, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil and transcutol. (Item 11) 11. The pharmaceutical composition according to any one of items 1 to 10, wherein the oil phase vehicle is a medium chain triglyceride. (Item 12) 12. The pharmaceutical composition according to any one of items 10 to 11, wherein the medium chain triglyceride is Labrafac™ Lipophile WL1349. (Item 13) 12. The pharmaceutical composition according to any one of items 10 to 11, wherein the medium chain triglyceride is Miglyol 812N. (Item 14) 14. The pharmaceutical composition according to any one of items 1 to 13, comprising an emulsifier. (Item 15) 15. The pharmaceutical composition according to any one of items 1 to 14, comprising about 5% to about 50% by weight of the emulsifier. (Item 16) 15. The pharmaceutical composition according to any one of items 1 to 14, comprising about 10% to about 30% by weight of the emulsifier. (Item 17) 15. The pharmaceutical composition according to any one of items 1 to 14, comprising about 15% to about 25% by weight of the emulsifier. (Item 18) 15. The pharmaceutical composition according to any one of items 1 to 14, comprising about 20% by weight of said emulsifier. (Item 19) 19. The pharmaceutical composition according to any one of items 1 to 18, wherein the emulsifier is selected from medium chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil and transcutol. (Item 20) 20. The pharmaceutical composition according to any one of items 1 to 19, wherein the emulsifier is propylene glycol dicaprylate / dicaproate. (Item 21) 21. The pharmaceutical composition according to any one of items 19 to 20, wherein the propylene glycol dicaprylate / dicaproate is Labrafac™ PG. (Item 22) 22. The pharmaceutical composition according to any one of items 1 to 21, comprising a non-ionic surfactant. (Item 23) 23. The pharmaceutical composition according to any one of items 1 to 22, comprising about 5% to about 50% by weight of the nonionic surfactant. (Item 24) 23. The pharmaceutical composition according to any one of items 1 to 22, comprising about 10% to about 30% by weight of the nonionic surfactant. (Item 25) 23. The pharmaceutical composition according to any one of items 1 to 22, comprising about 15% to about 25% by weight of the nonionic surfactant. (Item 26) 23. The pharmaceutical composition according to any one of items 1 to 22, comprising about 19% by weight of said non-ionic surfactant. (Item 27) 27. The pharmaceutical composition according to any one of items 1 to 26, wherein the non-ionic surfactant is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, Gelucire, lauroyl polyoxyl-32 glyceride, poloxamer, PEG-32 stearate and PEG-32 hydrogenated palm oil glyceride. (Item 28) 28. The pharmaceutical composition according to any one of items 1 to 27, wherein the nonionic surfactant is lauroyl polyoxyl-32 glyceride. (Item 29) 29. The pharmaceutical composition according to any one of items 27 to 28, wherein the lauroyl polyoxyl-32 glyceride is Gelucire® 44 / 14. (Item 30) 30. The pharmaceutical composition according to any one of items 1 to 29, comprising a solubilizer. (Item 31) 31. The pharmaceutical composition according to any one of items 1 to 30, comprising about 1% to about 50% by weight of the solubilizer. (Item 32) 31. The pharmaceutical composition according to any one of items 1 to 30, comprising about 1% to about 20% by weight of the solubilizer. (Item 33) 31. The pharmaceutical composition according to any one of items 1 to 30, comprising about 5% to about 15% by weight of the solubilizer. (Item 34) 31. The pharmaceutical composition according to any one of items 1 to 30, comprising about 11% by weight of said solubilizer. (Item 35) Item 36. The pharmaceutical composition according to any one of Items 1 to 34, wherein the solubilizer is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glyceride, and poloxamer. 36. The pharmaceutical composition according to any one of items 1 to 35, wherein the solubilizer is vitamin E polyethylene glycol succinate. (Item 37) 37. The pharmaceutical composition according to any one of items 35 to 36, wherein the vitamin E polyethylene glycol succinate is Kolliphor® TPGS. (Item 38) 37. The pharmaceutical composition according to any one of items 35 to 36, wherein the vitamin E polyethylene glycol succinate is vitamin E / TPGS260. (Item 39) (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof; (b) an oil phase vehicle; (c) emulsifiers; (d) nonionic surfactants, and (e) Solubilizer Item 1. The pharmaceutical composition according to item 1, comprising: (Item 40) (a) about 5% to about 15% by weight, based on the weight of the free base, of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof (b) about 35% to about 45% by weight of an oil phase vehicle (c) about 15% to about 25% by weight of an emulsifier (d) about 15% to about 25% by weight of a nonionic surfactant, and (e) about 5% to about 15% by weight of a solubilizing agent Item 1. The pharmaceutical composition according to item 1, comprising: (Item 41) (a) about 10% by weight, based on the weight of the free base, of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof; (b) about 39% by weight of an oil phase vehicle (c) about 20% by weight of an emulsifier (d) about 19% by weight of a nonionic surfactant, and (e) about 11% by weight of a solubilizing agent Item 1. The pharmaceutical composition according to item 1, comprising: (Item 42) (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) Medium-chain triglyceride components (c) Propylene Glycol Dicaprylate / Dicaproate Component (d) a lauroyl polyoxyl-32 glyceride component, and (e) Vitamin E polyethylene glycol succinate component Item 1. The pharmaceutical composition according to item 1, comprising: (Item 43) (a) about 5% by weight to about 15% by weight of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) about 35% to about 45% by weight of medium-chain triglycerides (c) about 15% to about 25% by weight of propylene glycol dicaprylate / dicaproate (d) about 15% to about 25% by weight of lauroyl polyoxyl-32 glyceride, and (e) The pharmaceutical composition according to item 1, comprising about 5% to about 15% by weight of vitamin E polyethylene glycol succinate. (Item 44) (a) approximately 10% by weight of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) approximately 39% by weight of medium-chain triglycerides (c) about 20% by weight of propylene glycol dicaprylate / dicaproate (d) about 19% by weight of lauroyl polyoxyl-32 glyceride, and (e) about 11% by weight of vitamin E polyethylene glycol succinate Item 1. The pharmaceutical composition according to item 1, comprising: (Item 45) 45. The pharmaceutical composition according to any one of items 1 to 44, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in crystalline form. (Item 46) 46. ​​A pharmaceutical composition according to any one of items 1 to 45, comprising the compound of formula (I) as a free base. (Item 47) 46. ​​The pharmaceutical composition of item 45, wherein the crystalline form comprises Form I of the compound of formula (I). (Item 48) 48. The pharmaceutical composition according to any one of items 1 to 47, formulated in unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 200 mg, by weight of the free base. (Item 49) 49. The pharmaceutical composition according to item 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 75 mg to about 150 mg by weight of the free base. (Item 50) 49. The pharmaceutical composition according to item 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 50 mg, based on the weight of the free base. (Item 51) 49. The pharmaceutical composition according to item 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 100 mg, based on the weight of the free base. (Item 52) 49. The pharmaceutical composition according to item 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 25 mg, based on the weight of the free base. (Item 53) 53. The pharmaceutical composition according to any one of items 1 to 52, in the form of a tablet, capsule, sachet, powder, granules, coated particles, coated tablets, enteric coated tablets, enteric coated capsules, melt strips or melt films. (Item 54) 54. A pharmaceutical composition according to any one of items 48 to 53, in tablet form. (Item 55) 54. The pharmaceutical composition according to any one of items 48 to 53, in capsule form. (Item 56) 56. The pharmaceutical composition according to any one of items 48 to 55, wherein the dosage form is coated. (Item 57) 57. A method for preparing a pharmaceutical composition according to any one of items 1 to 56, comprising the steps of: (a) heating a mixture of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer; (b) mixing the mixture of step (a) until a homogeneous mixture is obtained; and (c) mixing said compound of formula (I) or a pharmaceutically acceptable salt thereof with said homogenous mixture of step (b) until said compound of formula (I) or a pharmaceutically acceptable salt thereof is dissolved to form a composition. A method comprising: (Item 58) (d) encapsulating the composition of step (c) in a capsule shell to form a capsule; and (e) banding the capsules of step (d) in a mixture of a banding agent and a banding solvent. Item 57. The method of item 57, further comprising: (Item 59) (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (b) one or more of a sweetener, an antioxidant, and a flavoring agent; and (c) Liquid vehicle 1. A pharmaceutical composition in oral solution dosage form comprising: (Item 60) Item 60. The pharmaceutical composition according to item 59, comprising about 1 w / v% to about 50 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 61) Item 60. The pharmaceutical composition according to item 59, comprising about 1 w / v% to about 10 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 62) 60. The pharmaceutical composition according to item 59, comprising about 5 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 63) 63. A pharmaceutical composition according to any one of items 59 to 62, comprising a sweetener. (Item 64) 64. The pharmaceutical composition according to any one of items 59 to 63, comprising about 0.01 w / v% to about 1.5 w / v% of said sweetener. (Item 65) 64. The pharmaceutical composition according to any one of items 59 to 63, comprising about 0.1 w / v% to about 0.5 w / v% of said sweetener. (Item 66) 64. A pharmaceutical composition according to any one of items 59 to 63, comprising about 0.15 w / v% of said sweetener. (Item 67) 67. A pharmaceutical composition according to any one of items 59 to 66, wherein the sweetening agent is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol and avantame. (Item 68) 68. A pharmaceutical composition according to any one of items 59 to 67, wherein the sweetening agent is saccharin. (Item 69) 69. A pharmaceutical composition according to any one of items 59 to 68, comprising an antioxidant. (Item 70) 70. The pharmaceutical composition according to any one of items 59 to 69, comprising about 0.01 w / v% to about 1.5 w / v% of the antioxidant. (Item 71) 70. The pharmaceutical composition according to any one of items 59 to 69, comprising about 0.1 w / v% to about 0.5 w / v% of the antioxidant. (Item 72) 70. The pharmaceutical composition according to any one of items 59 to 69, comprising about 0.17 w / v% of said antioxidant. (Item 73) 73. The pharmaceutical composition according to any one of items 59 to 72, wherein the antioxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone and citric acid. (Item 74) 74. The pharmaceutical composition according to any one of items 59 to 73, wherein the antioxidant is butylated hydroxytoluene. (Item 75) 75. A pharmaceutical composition according to any one of items 59 to 74, comprising a flavoring agent. (Item 76) 76. The pharmaceutical composition according to any one of items 59 to 75, comprising about 0.01 w / v% to about 0.5 w / v% of said flavoring agent. (Item 77) 76. The pharmaceutical composition according to any one of items 59 to 75, comprising about 0.05 w / v% to about 0.2 w / v% of said flavoring agent. (Item 78) 76. A pharmaceutical composition according to any one of items 59 to 75, comprising about 0.10 w / v% of said flavoring agent. (Item 79) 79. The pharmaceutical composition according to any one of items 59 to 78, wherein the flavor is selected from FONA Orange flavor, FONA Juicy flavor, FONA Grape flavor, Firmenich SA Lemon flavor, Firmenich Tetrarome Orange flavor, IFF Cherry flavor and IFF Grape flavor. (Item 80) 80. The pharmaceutical composition of any one of items 59 to 79, wherein the flavor is FONA orange flavor. (Item 81) 81. The pharmaceutical composition according to any one of items 59 to 80, comprising about 50 w / v% to about 99.9 w / v% of said liquid vehicle. (Item 82) 81. The pharmaceutical composition according to any one of items 59 to 80, comprising about 92 w / v% to about 97 w / v% of said liquid vehicle. (Item 83) 81. The pharmaceutical composition according to any one of items 59 to 80, comprising about 94.6 w / v % of said liquid vehicle. (Item 84) 84. The pharmaceutical composition according to any one of items 59 to 83, wherein the liquid vehicle is selected from medium chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil and transcutol. (Item 85) 85. The pharmaceutical composition according to any one of items 59 to 84, wherein the liquid vehicle is a medium chain triglyceride. (Item 86) 86. The pharmaceutical composition according to any one of items 84 to 85, wherein the medium chain triglyceride is Labrafac Lipophile WL1349. (Item 87) 87. The pharmaceutical composition according to any one of items 59 to 86, further comprising a surfactant. (Item 88) 88. The pharmaceutical composition according to item 87, comprising about 1 w / v% to about 50 w / v% of the surfactant. (Item 89) 88. The pharmaceutical composition according to item 87, comprising about 10 w / v% to about 30 w / v% of the surfactant. (Item 90) 88. The pharmaceutical composition according to item 87, comprising about 20 w / v% of the surfactant. (Item 91) 91. The pharmaceutical composition according to any one of items 87 to 90, wherein the surfactant is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glyceride, sodium lauryl sulfate, poloxamer, corn oil PEG-6 ester and hydrogenated palm oil / palm kernel oil PEG-6 ester. (Item 92) 92. The pharmaceutical composition according to any one of items 87 to 91, wherein the surfactant is oleoyl polyoxyl-6 glyceride. (Item 93) 93. The pharmaceutical composition according to any one of items 91 to 92, wherein the oleoyl polyoxyl-6 glyceride is LABRAFIL M 1944 CS. (Item 94) 94. The pharmaceutical composition according to any one of items 59 to 93, comprising about 70 w / v% to about 80 w / v% of said liquid vehicle. (Item 95) 94. The pharmaceutical composition according to any one of items 59 to 93, comprising about 75 w / v % of said liquid vehicle. (Item 96) 96. The pharmaceutical composition according to any one of items 59 to 95, wherein the liquid vehicle is selected from medium chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil and transcutol. (Item 97) 97. The pharmaceutical composition of any one of items 59 to 96, wherein the liquid vehicle is a medium chain triglyceride. (Item 98) 97. The pharmaceutical composition according to any one of items 95 to 96, wherein the medium chain triglyceride is Labrafac Lipophile WL1349. (Item 99) (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof (b) Sweeteners (c) Antioxidants (d) flavoring agents, and (e) Liquid vehicle 60. The pharmaceutical composition according to item 59, comprising: (Item 100) 99. The pharmaceutical composition of claim 99, further comprising a surfactant. (Item 101) (a) about 4 w / v % to about 6 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w / v% to about 0.2 w / v% of a sweetener (c) about 0.1 w / v% to about 0.2 w / v% antioxidant (d) about 0.05% w / v to about 0.2% w / v of a flavoring agent, and (e) about 92 w / v% to about 97 w / v% liquid vehicle 60. The pharmaceutical composition according to item 59, comprising: (Item 102) (a) about 5 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w / v% sweetener (c) approximately 0.17 w / v% antioxidant (d) about 0.1 w / v% flavoring agent, and (e) Approximately 94.6 w / v% liquid vehicle 60. The pharmaceutical composition according to item 59, comprising: (Item 103) (a) about 4 w / v % to about 6 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w / v% to about 0.2 w / v% of a sweetener (c) about 0.1 w / v% to about 0.2 w / v% antioxidant (d) about 0.05 w / v% to about 0.2 w / v% of a flavoring agent; (e) about 15% w / v to about 25% w / v of a surfactant, and (f) About 70 w / v% to about 80 w / v% liquid vehicle 60. The pharmaceutical composition according to item 59, comprising: (Item 104) (a) about 5 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w / v% sweetener (c) approximately 0.17 w / v% antioxidant (d) about 0.1 w / v% flavoring agent; (e) about 20 w / v % surfactant, and (f) Approximately 75 w / v% liquid vehicle 60. The pharmaceutical composition according to item 59, comprising: (Item 105) (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof; (b) Saccharin (c) Butylated hydroxytoluene (d) FONA orange flavoring; and (e) Medium-chain triglycerides 60. The pharmaceutical composition according to item 59, comprising: (Item 106) 106. The pharmaceutical composition according to item 105, further comprising oleoyl polyoxyl-6 glyceride. (Item 107) (a) about 4 w / v % to about 6 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w / v% to about 0.2 w / v% saccharin (c) about 0.1 w / v% to about 0.2 w / v% butylated hydroxytoluene (d) about 0.05% w / v to about 0.2% w / v of FONA Orange Flavor, and (e) Approximately 92 w / v% to approximately 97 w / v% medium-chain triglycerides 107. The pharmaceutical composition according to item 106, comprising: (Item 108) (a) about 5 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) approximately 0.15 w / v% saccharin (c) about 0.17 w / v% butylated hydroxytoluene (d) about 0.1 w / v% FONA orange flavor; and (e) Approximately 94.6 w / v% medium-chain triglycerides 60. The pharmaceutical composition according to item 59, comprising: (Item 109) (a) about 4 w / v % to about 6 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w / v% to about 0.2 w / v% saccharin (c) about 0.1 w / v% to about 0.2 w / v% butylated hydroxytoluene (d) about 0.05 w / v% to about 0.2 w / v% FONA Orange Flavor (e) about 15% w / v to about 25% w / v of oleoyl polyoxyl-6 glyceride, and (f) Approximately 70 w / v% to approximately 80 w / v% medium-chain triglycerides 60. The pharmaceutical composition according to item 59, comprising: (Item 110) (a) about 5 w / v % of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) approximately 0.15 w / v% saccharin (c) about 0.17 w / v% butylated hydroxytoluene (d) about 0.1 w / v% FONA orange flavoring (e) about 20 w / v% oleoyl polyoxyl-6 glyceride, and (f) Approximately 75 w / v% medium-chain triglycerides 60. The pharmaceutical composition according to item 59, comprising: (Item 111) 111. A pharmaceutical composition according to any one of items 59 to 110, comprising the compound of formula (I) as a free base. (Item 112) 112. The pharmaceutical composition of any one of items 59 to 111, formulated in a unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg / mL to about 200 mg / mL by weight of the free base. (Item 113) The pharmaceutical composition according to Item 112, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 75 mg / mL to about 150 mg / mL by weight of the free base. Item 113. The pharmaceutical composition of item 112, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 50 mg / mL, based on the weight of the free base. (Item 115) 113. The pharmaceutical composition according to item 112, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 100 mg / mL, based on the weight of the free base. (Item 116) 57. The pharmaceutical composition according to any one of items 1 to 56, having a viscosity of between about 15 and about 40 centipoise at about 45°C. (Item 117) 117. A method for preparing a pharmaceutical composition according to any one of items 59 to 116, comprising the steps of: (a) mixing a liquid vehicle with a sweetener; (b) mixing the mixture of step (a) with an antioxidant and a flavoring agent; (c) mixing said compound of formula (I) or a pharmaceutically acceptable salt thereof with said mixture of step (b); and (d) mixing the mixture of step (c) with an additional portion of the liquid vehicle. A method comprising: (Item 118) Item 118. The method of claim 117, wherein step (a) comprises mixing a liquid vehicle with a sweetener and a surfactant. (Item 119) A compound having the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and a polymer selected from a neutral polymer, an enteric polymer, and a pyrrolidone polymer; 1. A spray-dried dispersion comprising: A spray-dried dispersion, wherein the weight ratio of the compound of formula (I) to the polymer is from about 1:1 to about 1:9. (Item 120) Item 121. The spray-dried dispersion of item 119, wherein the neutral polymer is selected from hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC). 120. The spray-dried dispersion according to item 119, wherein the enteric polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), amino methacrylate copolymers, ammonioalkyl methacrylate copolymers and methacrylic copolymers. (Item 122) Item 123. The spray-dried dispersion of item 119, wherein the pyrrolidone polymer is selected from polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone vinyl acetate (PVP / VA). Item 124. The spray-dried dispersion according to Item 122, wherein the pyrrolidone polymer is PVP / VA. 124. The spray-dried dispersion of item 123, wherein the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 40:60 to about 60:40. (Item 125) 125. The spray-dried dispersion of item 124, wherein the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 60:40. (Item 126) The copolymer has the following structure: [ka] 126. The spray-dried dispersion according to any one of items 122 to 125, having the formula: wherein the value of n is from about 1 to about 2 times the value of m. (Item 127) 127. The spray-dried dispersion of item 126, wherein the copolymer is copovidone and the value of n is about 1.16 times the value of m. (Item 128) 127. The spray-dried dispersion of item 126, wherein the copolymer is copovidone having an average molecular weight of about 45,000 to about 70,000. (Item 129) A compound having the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and A polymer that is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the following structure: [ka] wherein the value of n is about 1 to about 2 times the value of m, and the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 60:40. 1. A spray-dried dispersion comprising: A spray-dried dispersion, wherein the weight ratio of the compound of formula (I) to the copolymer is from about 1:1 to about 1:9. (Item 130) 130. The spray-dried dispersion according to any one of items 119 to 129, wherein the compound of formula (I) and the polymer together form uniform particles. (Item 131) The particles have a particle size distribution D of about 5 μm to about 100 μm. 50 131. The spray-dried dispersion according to any one of items 119 to 130, having (Item 132) The particles have a particle size distribution D of about 10 μm to about 50 μm. 50 132. The spray-dried dispersion according to any one of items 119 to 131, having (Item 133) The particles have a particle size distribution D of about 15 μm to about 30 μm. 50 133. The spray-dried dispersion according to any one of items 119 to 132, having (Item 134) 134. The spray-dried dispersion according to any one of items 119 to 133, wherein the weight ratio of the compound of formula (I) to the polymer is from about 1:1.5 to about 1:9. (Item 135) 135. The spray-dried dispersion according to any one of items 119 to 134, wherein the weight ratio of the compound of formula (I) to the polymer is from about 1:2.5 to about 1:4. (Item 136) 136. The spray-dried dispersion according to any one of items 119 to 135, wherein the weight ratio of the compound of formula (I) to the polymer is about 1:3. (Item 137) 137. The spray-dried dispersion of any one of items 119 to 136, wherein the particles have a residual solvent content of less than about 2% by weight. (Item 138) 138. The spray-dried dispersion of any one of items 119 to 137, wherein the particles have a residual solvent content of less than about 1 wt.%. (Item 139) 139. The spray-dried dispersion of any one of items 119 to 138, wherein the particles have a residual solvent content of about 0.5 wt% or less. (Item 140) 140. The spray-dried dispersion according to any one of items 119 to 139, wherein the compound of formula (I) in the dispersion is substantially amorphous. (Item 141) 141. A pharmaceutical composition comprising the spray-dried dispersion according to any one of items 119 to 140 and one or more pharmaceutically acceptable excipients. (Item 142) Item 142. The pharmaceutical composition according to item 141, wherein the spray-dried dispersion is present in an amount of about 20% to about 90% w / w of the composition. (Item 143) Item 143. The pharmaceutical composition according to item 142, wherein the spray-dried dispersion is present in an amount of about 40% to about 80% w / w of the composition. (Item 144) Item 142. The pharmaceutical composition according to item 141, wherein the spray-dried dispersion is present in an amount of about 1% to about 20% w / w of the composition. (Item 145) 145. The pharmaceutical composition of claim 144, wherein the spray-dried dispersion is present in an amount of about 13% w / w of the composition. (Item 146) 146. The pharmaceutical composition according to any one of items 141 to 145, wherein the pharmaceutical excipient is selected from the group consisting of fillers, lubricants and combinations thereof. (Item 147) 147. The pharmaceutical composition of claim 146, wherein the filler is selected from the group consisting of binders, diluents, disintegrants, glidants, surfactants, and combinations thereof. (Item 148) 148. The pharmaceutical composition according to any one of items 141 to 147, formulated in unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of from about 5 mg to about 200 mg. (Item 149) Item 149. The pharmaceutical composition according to item 148, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 75 mg to about 150 mg. (Item 150) 149. The pharmaceutical composition according to item 149, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 50 mg. (Item 151) 149. The pharmaceutical composition according to item 149, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 100 mg. (Item 152) 152. The pharmaceutical composition according to any one of items 141 to 151, wherein the pharmaceutical excipient is selected from the group consisting of glidants, fillers, disintegrants, lubricants and combinations thereof. (Item 153) 153. A pharmaceutical composition according to any one of items 141 to 152, comprising a glidant. (Item 154) 154. The pharmaceutical composition according to any one of items 152 to 153, comprising about 0.1 w / w% to about 5 w / w% of said glidant. (Item 155) 154. The pharmaceutical composition according to any one of items 152 to 153, comprising about 0.1 w / w% to about 1 w / w% of said glidant. (Item 156) 154. A pharmaceutical composition according to any one of items 152 to 153, comprising about 0.67 w / w% of said glidant. (Item 157) 157. A pharmaceutical composition according to any one of items 152 to 156, wherein the glidant is selected from calcium silicate, silicon dioxide and talc. (Item 158) 158. The pharmaceutical composition of any one of items 152 to 157, wherein the glidant is calcium silicate. (Item 159) 159. The pharmaceutical composition according to any one of items 141 to 158, comprising a filler. (Item 160) 159. The pharmaceutical composition according to any one of items 152 to 159, comprising from about 30 w / w% to about 99 w / w% of said filler. (Item 161) 159. The pharmaceutical composition according to any one of items 152 to 159, comprising about 50 w / w% to about 90 w / w% of said filler. (Item 162) 159. A pharmaceutical composition according to any one of items 152 to 159, comprising about 75.5 w / w% of said filler. (Item 163) 163. The pharmaceutical composition according to any one of items 152 to 162, wherein the filler is selected from mannitol, microcrystalline cellulose, lactose, starch, isomalt, silicified microcrystalline cellulose, dicalcium phosphate, maltodextrin and combinations thereof. (Item 164) 164. The pharmaceutical composition according to any one of items 152 to 163, wherein the filler is a combination of mannitol and microcrystalline cellulose. (Item 165) 165. The pharmaceutical composition according to any one of items 163 to 164, comprising about 30 w / w% to about 80 w / w% mannitol. (Item 166) 165. The pharmaceutical composition according to any one of items 163 to 164, comprising about 50 w / w% to about 60 w / w% mannitol. (Item 167) 165. A pharmaceutical composition according to any one of items 163 to 164, comprising about 56 w / w% mannitol. (Item 168) 168. The pharmaceutical composition according to any one of items 163 to 167, comprising about 1 w / w% to about 50 w / w% microcrystalline cellulose. (Item 169) 168. The pharmaceutical composition according to any one of items 163 to 167, comprising about 10 w / w% to about 30 w / w% microcrystalline cellulose. (Item 170) 168. A pharmaceutical composition according to any one of items 163 to 167, comprising about 20 w / w% microcrystalline cellulose. (Item 171) 168. A pharmaceutical composition according to any one of items 163 to 167, comprising about 56 w / w% mannitol and about 20 w / w% microcrystalline cellulose. (Item 172) 172. The pharmaceutical composition according to any one of items 141 to 171, comprising a disintegrant. (Item 173) 173. The pharmaceutical composition according to any one of items 152 to 172, comprising about 1 w / w% to about 30 w / w% of said disintegrant. (Item 174) 173. The pharmaceutical composition according to any one of items 152 to 172, comprising about 5 w / w% to about 15 w / w% of said disintegrant. (Item 175) 173. The pharmaceutical composition according to any one of items 152 to 172, comprising about 10 w / w% of said disintegrant. (Item 176) 176. The pharmaceutical composition according to any one of items 152 to 175, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone and sodium bicarbonate. (Item 177) 177. A pharmaceutical composition according to any one of items 152 to 176, wherein the disintegrant is croscarmellose sodium. (Item 178) 178. A pharmaceutical composition according to any one of items 141 to 177, comprising a lubricant. (Item 179) 179. The pharmaceutical composition according to any one of items 152 to 178, comprising about 0.1 w / w% to about 10 w / w% of said lubricant. (Item 180) 179. The pharmaceutical composition according to any one of items 152 to 178, comprising about 0.1 w / w% to about 1 w / w% of said lubricant. (Item 181) 179. A pharmaceutical composition according to any one of items 152 to 178, comprising about 0.5 w / w% of said lubricant. (Item 182) 182. A pharmaceutical composition according to any one of items 152 to 181, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid, sodium lauryl sulphate, sodium oleate, glyceryl behenate and talc. (Item 183) 183. A pharmaceutical composition according to any one of items 152 to 182, wherein the lubricant is sodium stearyl fumarate. (Item 184) (a) a spray-dried dispersion according to any one of items 119 to 140 (b) Glidants (c) fillers, and (d) Disintegrants 184. The pharmaceutical composition according to any one of items 141 to 183, comprising (Item 185) (a) from about 1 w / w% to about 20 w / w% of the spray-dried dispersion according to any one of items 119 to 140 (b) about 0.1 w / w% to about 1 w / w% of a glidant (c) about 50 w / w% to about 90 w / w% filler, and (d) about 5 w / w% to about 0.2 w / w% of a disintegrant 184. The pharmaceutical composition according to any one of items 141 to 183, comprising (Item 186) (a) about 13 w / w% of the spray-dried dispersion according to any one of items 119 to 140 (b) about 0.67 w / w% glidant (c) about 75.5 w / w% filler, and (d) about 10 w / w% disintegrant 184. The pharmaceutical composition according to any one of items 141 to 183, comprising (Item 187) (a) The spray-dried dispersion of Example 3 (b) calcium silicate (c) a combination of mannitol and microcrystalline cellulose, and (d) Croscarmellose sodium 184. The pharmaceutical composition according to any one of items 141 to 183, comprising (Item 188) (a) about 1 w / w% to about 20 w / w% of the spray-dried dispersion of Example 3 (b) about 0.1 w / w% to about 1 w / w% calcium silicate (c) about 50 w / w% to about 60 w / w% mannitol and about 10 w / w% to about 30 w / w% microcrystalline cellulose, and (d) about 5 w / w% to about 0.2 w / w% croscarmellose sodium 188. The pharmaceutical composition according to item 187, comprising: (Item 189) (a) about 13 w / w% of the spray-dried dispersion of Example 3 (b) about 0.67 w / w% calcium silicate (c) about 56 w / w% mannitol and about 20 w / w% microcrystalline cellulose, and (d) approximately 10 w / w% croscarmellose sodium 189. The pharmaceutical composition according to item 188, comprising: (Item 190) Item 191. The pharmaceutical composition according to any one of items 141 to 189, formulated as a tablet, capsule, sachet, powder, granules, coated particles, coated tablet, enteric coated tablet, enteric coated capsule, melt strip or melt film. 191. The pharmaceutical composition according to item 190, in tablet form. (Item 192) 191. The pharmaceutical composition according to item 190, in capsule form. (Item 193) 191. The pharmaceutical composition according to item 190, in the form of a sachet. (Item 194) 191. The pharmaceutical composition according to item 190, in the form of granules. (Item 195) Item 196. The pharmaceutical composition according to any one of Items 190 to 192, which is coated. 141. A method for preparing a spray-dried dispersion according to any one of items 119 to 140, comprising the steps of: dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer in an organic solvent to form a solution; and spray drying the solution to form the spray-dried dispersion, wherein the spray drying forms uniform particles of the compound of formula (I) and the polymer. A method comprising: (Item 197) 197. The method of claim 196, comprising removing the organic solvent after forming the spray-dried dispersion by drying the spray-dried dispersion. (Item 198) Item 198. The method of item 197, wherein the spray-dried dispersion is dried using a convection tray dryer. (Item 199) Item 200. The method of any one of Items 196 to 198, wherein the organic solvent is acetone. 199. The method according to any one of items 196 to 199, wherein the spray dryer inlet temperature is from about 60°C to about 80°C. (Item 201) 201. The method of claim 200, wherein the spray dryer inlet temperature is about 72°C. (Item 202) 202. The method according to any one of items 196 to 201, wherein the spray dryer outlet temperature is from about 25°C to about 45°C. (Item 203) 203. The method of claim 202, wherein the spray dryer outlet temperature is about 35°C. (Item 204) 204. The method of any one of items 196 to 203, wherein the uniform particles comprise a bulk density of less than about 0.2 g / mL. (Item 205) 205. The method of claim 204, wherein the uniform particles comprise a bulk density of less than about 0.15 g / mL. (Item 206) 206. The method of any one of items 196 to 205, wherein the uniform particles comprise a tap density of less than about 0.3 g / mL. (Item 207) 207. The method of claim 206, wherein the uniform particles comprise a tap density of less than about 0.25 g / mL. (Item 208) 141. A method for preparing a pharmaceutical composition comprising combining the spray-dried dispersion according to any one of items 119 to 140 with one or more pharmaceutically acceptable excipients. (Item 209) (a) blending the spray-dried dispersion according to any one of items 119 to 140 with a glidant (b) further blending the blend of step (a) with a filler and a disintegrant. (c) screening the blend of step (b) to break up agglomerates and aid in blend uniformity. (d) further blending the intragranular blend of step (c). (e) compressing the intragranular blend of step (d) by roller compaction to form granules; and (f) milling the ribbons from the roller compaction into granules of step (e). Item 209. The method of Item 208, comprising: (Item 210) 196. A method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the spray-dried dispersion of any one of items 119 to 140 or the pharmaceutical composition of any one of items 141 to 195. (Item 211) 211. The method of claim 210, wherein the spray-dried dispersion or the pharmaceutical composition is administered to the subject in a fed state. (Item 212) 212. The method of claim 210 or 211, wherein the spray-dried dispersion or the pharmaceutical composition is administered to the subject together with a nutritional composition. (Item 213) 213. The method of claim 212, wherein the nutritional composition is a liquid dietary supplement containing 1500 calories per liter with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrates. (Item 214) 214. The method of claim 212 or 213, wherein the nutritional composition is administered in an amount of about 8 fluid ounces. (Item 215) 215. The method of any one of items 212 to 214, wherein the nutritional composition is administered within 30 minutes of administering the spray-dried dispersion or the pharmaceutical composition. (Item 216) 216. The method according to any one of items 211 to 215, wherein administration of the spray-dried dispersion or the pharmaceutical composition shows a positive food effect. (Item 217) The positive food effect is measured by comparing oral administration of the spray-dried dispersion or pharmaceutical composition in the fed and fasted states. max 217. The method of claim 216, wherein the IL-10 is measured in terms of IL-10, AUC, AUC, or a combination thereof. (Item 218) 218. The method of any one of items 211 to 217, wherein the ratio of AUC in the fed state to AUC in the fasted state is about 5 to about 10. (Item 219) C in the fed state max C in the fasting state max 218. The method according to any one of items 211 to 217, wherein the ratio of (Item 220) 219. The method of any one of items 210 to 219, wherein the subject is a pediatric subject. (Item 221) 196. A method for improving gastrointestinal absorption of a compound of formula (I) in a subject, comprising orally administering to said subject a pharmaceutical composition according to any one of items 141 to 195, wherein said improvement is an improvement over oral administration of said compound of formula (I) that is not prepared as a spray-dried dispersion. (Item 222) 222. The method of claim 221, wherein the subject is a pediatric subject. (Item 223) 196. A method for improving the oral bioavailability of a compound of formula (I) in a subject, comprising orally administering to said subject a pharmaceutical composition according to any one of items 141 to 195, wherein said improvement is an improvement over oral administration of said compound of formula (I) that is not prepared as a spray-dried dispersion. (Item 224) 224. The method of claim 223, wherein the subject is a pediatric subject. (Item 225) 141. The spray-dried dispersion according to any one of items 119 to 140, which is formulated for oral administration and which shows a positive food effect when administered orally. (Item 226) 226. The spray-dried dispersion according to item 225, having a ratio of AUC in the fed state to AUC in the fasted state of about 5 to about 10. (Item 227) C in the feeding state is about 5 to about 10 max C in the fasting state max 226. The spray-dried dispersion according to item 225, having a ratio to (Item 228) A crystalline salt which is the p-toluenesulfonic acid salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine. (Item 229) 229. The salt according to item 228 having form 1 of the compound of formula (I). (Item 230) 220. The salt according to item 228 or item 229, having an X-ray powder diffraction pattern substantially as shown in Figure 27. (Item 231) 231. The salt according to any one of items 228 to 230, having a DSC thermogram substantially as depicted in Figure 28. (Item 232) 232. The salt according to any one of items 228 to 231, having a thermogravimetric analysis (TGA) thermogram substantially as depicted in Figure 28. (Item 233) 233. The salt according to any one of items 228 to 232, having at least one X-ray powder diffraction (XRPD) peak selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees two-theta (±0.2 degrees). (Item 234) 233. The salt according to any one of items 228 to 232, having at least two X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees two-theta (±0.2 degrees). (Item 235) 233. The salt according to any one of items 228 to 232, having at least three X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees two-theta (±0.2 degrees). (Item 236) 233. The salt according to any one of items 228 to 232, having at least four X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees two-theta (±0.2 degrees). (Item 237) 233. The salt according to any one of items 228 to 232, having characteristic X-ray powder diffraction (XRPD) peaks at 9.1, 11.3, 13.2, 16.3 and 21.1 degrees two theta (±0.2 degrees). (Item 238) 238. The salt according to any one of items 228 to 237, having an endothermic peak (22.2 J / g) with an onset of melting at about 156° C. in a differential scanning calorimetry (DSC) thermogram. (Item 239) 1. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 240) 239. The method of claim 239, wherein the decrease in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during circadian release on a day before administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof with the level of the biomarker measured during circadian release on a day after administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 241) 241. The method of claim 240, wherein the circadian release occurs between 2:00 AM and 10:00 AM. (Item 242) 242. The method of any one of items 239 to 241, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered 3 to 8 hours before the circadian release of the biomarker. (Item 243) 243. The method of any one of items 239 to 242, wherein the level of 17-hydroxyprogesterone is reduced by at least 25%. (Item 244) 243. The method of any one of items 239 to 242, wherein the level of 17-hydroxyprogesterone is reduced by at least 50%. (Item 245) 245. The method of any one of items 239 to 244, wherein the level of adrenocorticotropic hormone is reduced by at least 25%. (Item 246) 245. The method of any one of items 239 to 244, wherein the level of adrenocorticotropic hormone is reduced by at least 40%. (Item 247) 245. The method of any one of items 239 to 244, wherein the level of adrenocorticotropic hormone is reduced by at least 50%. (Item 248) 248. The method of any one of items 239 to 247, wherein the level of androstenedione is reduced by at least 25%. (Item 249) 248. The method of any one of items 239 to 247, wherein the level of androstenedione is reduced by at least 30%. (Item 250) 248. The method of any one of items 239 to 247, wherein the level of androstenedione is reduced by at least 50%. (Item 251) 251. The method of any one of items 239 to 250, wherein the level of 17-hydroxyprogesterone is reduced by at least 50% and the level of androstenedione is reduced by at least 50%. (Item 252) 252. The method of any one of items 239 to 251, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 253) 253. The method of any one of items 239 to 252, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form. (Item 254) 1. A method of reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and impaired growth in a subject with classical congenital adrenal hyperplasia, comprising: administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in an amount sufficient to decrease the level of androstenedione in the subject. A method comprising: (Item 255) 255. The method of claim 254, wherein the growth dysfunction is selected from one or more of accelerated height growth rate, accelerated weight gain rate, or accelerated bone age. (Item 256) 256. The method of claim 254 or 255, wherein the androstenedione is reduced by at least 25%. (Item 257) 256. The method of claim 254 or 255, wherein the androstenedione is reduced by at least 30%. (Item 258) 256. The method of claim 254 or 255, wherein the androstenedione is reduced by at least 50%. (Item 259) A method for reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia, comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 260) 259. The method of claim 259, wherein the one or more biomarkers of congenital adrenal hyperplasia are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 261) 1. A method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 262) 262. The method of claim 261, wherein the corticosteroid is a glucocorticoid. (Item 263) 1. A method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising the step of administering to the subject a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's disease, or the like. syndrome, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection. (Item 264) 264. The method of any one of items 259 to 263, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% compared to the level before administration. (Item 265) The method of any one of Items 259 to 264, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce androstenedione levels by at least 30% compared to pre-administration levels. (Item 266) 265. The method of any one of items 259 to 264, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to (a) reduce 17-hydroxyprogesterone (17-OHP) levels by at least 50% compared to pre-administration levels, and (b) reduce androstenedione levels by at least 30% compared to pre-administration levels. (Item 267) 267. The method of any one of items 259 to 266, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 268) 268. The method of any one of items 259 to 267, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 269) 269. The method of any one of items 259 to 268, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form. (Item 270) 1. A method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have an elevated level of the one or more biomarkers, administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. A method comprising: (Item 271) (iv) measuring the level of the one or more biomarkers in a biological sample obtained from the subject after administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof to determine whether the subject has a decreased level of the one or more biomarkers compared to the measurement in step (i). (Item 272) (v) The method of item 271, further comprising the step of continuing the administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof if the subject has a decreased level of the one or more biomarkers. (Item 273) 273. The method of claim 271 or 272, wherein steps (i) and (iv) are performed on biological samples taken from said subject in a similar manner and within the same time period of the day. (Item 274) 274. The method of any one of items 271 to 273, wherein steps (i) and (iv) are performed on a biological sample taken from the subject within the time period of a day between 2:00 AM and 10:00 AM. (Item 275) 274. The method of any one of items 271 to 273, wherein steps (i) and (iv) are performed on a biological sample taken from the subject within the time frame of 6:00 AM to 10:00 AM. (Item 276) 276. The method of any one of items 271 to 275, wherein steps (i) and (iv) comprise measuring levels of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 277) 276. The method of any one of items 271 to 275, wherein steps (i) and (iv) comprise measuring levels of (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 278) 278. The method of any one of items 270 to 277, wherein step (i) comprises measuring the level of 17-hydroxyprogesterone (17-OHP), and the level of 17-hydroxyprogesterone (17-OHP) is elevated if it is greater than or equal to 1,000 ng / dL. (Item 279) 279. The method of any one of items 270 to 278, wherein step (i) comprises measuring the level of androstenedione, and the level of androstenedione is elevated if it is higher than 200 ng / dL. (Item 280) 279. The method of any one of items 270 to 279, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 281) 279. The method of any one of items 270 to 279, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 282) 282. The method of any one of items 270 to 281, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in its free base form. (Item 283) 284. A method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the subject is in a fed state. 284. The method of claim 283, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered to the subject together with a nutritional composition. (Item 285) 285. The method of claim 284, wherein the nutritional composition is a liquid dietary supplement containing 1500 calories per liter with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrates. (Item 286) 286. The method of claim 284 or 285, wherein the nutritional composition is administered in an amount of about 8 fluid ounces. (Item 287) 287. The method of any one of items 284 to 286, wherein the nutritional composition is administered within 30 minutes of administering the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 288) 196. The pharmaceutical composition of any one of items 1 to 56, 59 to 116 or 141 to 195, for use in a method for treating congenital adrenal hyperplasia (CAH) in a subject. (Item 289) 289. The pharmaceutical composition for use according to item 288, wherein the subject is in a fed state. (Item 290) 280. The pharmaceutical composition for use according to item 288 or item 289, wherein the subject is administered the pharmaceutical composition together with a nutritional composition. (Item 291) 291. The pharmaceutical composition for use according to item 290, wherein the nutritional composition is a liquid dietary supplement containing about 1000 to about 2000 calories per liter having a fat content of greater than about 30%. (Item 292) 291. The pharmaceutical composition for use according to item 290, wherein the nutritional composition is a liquid dietary supplement containing 1500 calories per liter with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrates. (Item 293) 293. The pharmaceutical composition for use according to any one of items 290 to 292, wherein the nutritional composition is administered in an amount of about 6 to about 12 fluid ounces. (Item 294) 294. The pharmaceutical composition for use according to any one of items 290 to 293, wherein the nutritional composition is administered in an amount of about 8 fluid ounces. (Item 295) 295. The pharmaceutical composition for use according to any one of items 290 to 294, wherein said nutritional composition is administered within 30 minutes of administering said pharmaceutical composition. (Item 296) 296. The pharmaceutical composition for use according to any one of items 289 to 295, wherein administration of the pharmaceutical composition shows a positive food effect. (Item 297) The positive food effect is measured by comparing oral administration of the pharmaceutical composition in the fed and fasted states to determine the C of the compound of formula (I). max297. The pharmaceutical composition for use according to item 296, wherein the saturation is measured in terms of saturation, AUC, or a combination thereof. (Item 298) 298. The pharmaceutical composition for use according to any one of items 289 to 297, wherein the ratio of AUC of the compound of formula (I) in the fed state to AUC of the compound of formula (I) in the fasted state is from about 1 to about 4 or from about 5 to about 10. (Item 299) C of the compound of formula (I) in the fed state max C of the compound of formula (I) in a fasting state max 298. The pharmaceutical composition for use according to any one of items 289 to 297, wherein the ratio of (Item 300) 298. The pharmaceutical composition for use according to any one of items 289 to 297, wherein the ratio of AUC of the compound of formula (I) in the fed state to AUC of the compound of formula (I) in the fasted state is from about 1.5 to about 3. (Item 301) C of the compound of formula (I) in the fed state max C of the compound of formula (I) in a fasting state max 298. The pharmaceutical composition for use according to any one of items 289 to 297, wherein the ratio of (Item 302) 302. The pharmaceutical composition for use according to any one of items 288 to 301, wherein the subject is a pediatric subject. (Item 303) 296. A pharmaceutical composition for use according to any one of items 289 to 295, which when administered orally shows a positive food effect. (Item 304) 304. The pharmaceutical composition for use according to Item 303, wherein the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4 or about 5 to about 10. (Item 305) The compound of formula (I) has a C in the fed state of about 1 to about 4 or about 5 to about 10. max C in the fasting statemax 304. The pharmaceutical composition for use according to item 303, having a ratio of: (Item 306) 304. The pharmaceutical composition for use according to Item 303, wherein the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1.5 to about 3. (Item 307) The compound of formula (I) has a C in the fed state of about 1.5 to about 3. max C in the fasting state max 304. The pharmaceutical composition for use according to item 303, having a ratio of: (Item 308) 308. The pharmaceutical composition for use according to any one of items 288 to 307, which is administered to the subject with a meal. (Item 309) 309. The pharmaceutical composition for use according to item 308, wherein the meal is a high-fat meal. (Item 310) 309. The pharmaceutical composition for use according to item 308, wherein the diet is a low-fat diet. (Item 311) 311. The pharmaceutical composition for use according to any one of items 308 to 310, wherein the composition is administered within about 5 minutes after starting the meal. (Item 312) 312. The pharmaceutical composition for use according to any one of items 308 to 311, wherein the meal is dinner. (Item 313) 312. The pharmaceutical composition for use according to any one of items 308 to 311, wherein the meal is breakfast. (Item 314) 314. The pharmaceutical composition for use according to any one of items 308 to 313, wherein administration of said pharmaceutical composition shows a positive food effect. (Item 315) The positive food effect is measured by comparing oral administration of the pharmaceutical composition in the fed and fasted states to determine the C of the compound of formula (I). max 315. The pharmaceutical composition for use according to item 314, wherein the saturation is measured in terms of saturation, AUC, or a combination thereof. (Item 316) 316. The pharmaceutical composition for use according to any one of items 308 to 315, wherein the ratio of AUC of said compound of formula (I) in the fed state to AUC of said compound of formula (I) in the fasted state is from about 1 to about 4 or from about 5 to about 10. (Item 317) C of the compound of formula (I) in the fed state max C of the compound of formula (I) in a fasting state max 317. The pharmaceutical composition for use according to any one of items 308 to 316, wherein the ratio of (Item 318) 316. The pharmaceutical composition for use according to any one of items 308 to 315, wherein the ratio of AUC of the compound of formula (I) in the fed state to AUC of the compound of formula (I) in the fasted state is from about 1.5 to about 3. (Item 319) C of the compound of formula (I) in the fed state max C of the compound of formula (I) in a fasting state max 319. The pharmaceutical composition for use according to any one of items 308 to 315 or 318, wherein the ratio of (Item 320) A pharmaceutical composition for use according to any one of items 288 to 319, comprising about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 321) A pharmaceutical composition for use according to any one of items 288 to 319, comprising about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 322) A pharmaceutical composition for use according to any one of items 288 to 319, comprising about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 323) 319. A pharmaceutical composition for use according to any one of items 288 to 319, comprising about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 324) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 325) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 326) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 327) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 328) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 329) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering a daily dose of the pharmaceutical composition comprising about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base. (Item 330) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering the pharmaceutical composition twice a day at a dose of about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 331) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering the pharmaceutical composition twice a day at a dose of about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 332) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering the pharmaceutical composition twice a day at a dose of about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. (Item 333) 319. The pharmaceutical composition for use according to any one of items 288 to 319, wherein the method comprises administering the pharmaceutical composition at a dose of about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight of the free base, twice a day. (Item 334) 334. The pharmaceutical composition for use according to any one of items 288 to 333, wherein the subject is simultaneously receiving a dose of a glucocorticoid. (Item 335) 335. The pharmaceutical composition for use according to item 334, wherein the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate and deoxycorticosterone acetate. (Item 336) 336. A pharmaceutical composition for use according to item 334 or 335, wherein the glucocorticoid is cortisol (hydrocortisone). (Item 337) 336. A pharmaceutical composition for use according to item 334 or 335, wherein the glucocorticoid is cortisone. (Item 338) 336. A pharmaceutical composition for use according to item 334 or 335, wherein the glucocorticoid is prednisone. (Item 339) 339. The pharmaceutical composition for use according to any one of items 334 to 338, wherein the dose of glucocorticoid is measured in hydrocortisone equivalents. (Item 340) 339. The pharmaceutical composition for use according to any one of items 334 to 339, wherein the dose of glucocorticoid is measured in hydrocortisone equivalents as a multiple of the upper normal limit of physiological dosing. (Item 341) 341. The pharmaceutical composition for use according to any one of items 334 to 340, wherein the dose of glucocorticoid is a physiological dose when measured after a period of administration of the pharmaceutical composition. (Item 342) The dose of the glucocorticoid is about 4 to about 12 mg / m when measured after the administration period of the pharmaceutical composition. 2 341. The pharmaceutical composition for use according to any one of items 334 to 340, wherein the physiological dose is 100 mg / day. (Item 343) The dose of the glucocorticoid is about 4 to about 9 mg / m when measured after the administration period of the pharmaceutical composition. 2 341. The pharmaceutical composition for use according to any one of items 334 to 340, wherein the physiological dose is 100 mg / day. (Item 344) The dose of the glucocorticoid is about 8 mg / m as measured after the administration period of the pharmaceutical composition. 2 341. The pharmaceutical composition for use according to any one of items 334 to 340, wherein the physiological dose is less than 100 mg / day. (Item 345) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 10% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 346) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the subject's dose of the glucocorticoid is reduced by about 20% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 347) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 30% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 348) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 40% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 349) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 350) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 60% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 351) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 70% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 352) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by less than about 20% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 353) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the dose of the glucocorticoid in the subject is reduced by about 20% to about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 354) 345. The pharmaceutical composition for use according to any one of items 334 to 344, wherein the subject's dose of the glucocorticoid is reduced by more than about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the dose of the glucocorticoid is relative to the dose of the glucocorticoid before administration of the pharmaceutical composition. (Item 355) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein the level of 17-hydroxyprogesterone is reduced by at least about 25% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of the pharmaceutical composition. (Item 356) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein the level of 17-hydroxyprogesterone is reduced by at least about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of the pharmaceutical composition. (Item 357) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein the level of 17-hydroxyprogesterone is less than about 1.5 times the upper normal limit after a period of administration of the pharmaceutical composition. (Item 358) Item 359. The pharmaceutical composition for use according to any one of items 288 to 354, wherein the level of 17-hydroxyprogesterone is within normal limits after a period of administration of the pharmaceutical composition. 359. The pharmaceutical composition for use according to any one of items 288 to 358, wherein the level of adrenocorticotropic hormone is reduced by at least about 25% after a period of administration of the pharmaceutical composition, wherein said reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (Item 360) 359. The pharmaceutical composition for use according to any one of items 288 to 358, wherein the level of adrenocorticotropic hormone is reduced by at least about 40% after a period of administration of the pharmaceutical composition, wherein said reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (Item 361) 359. The pharmaceutical composition for use according to any one of items 288 to 358, wherein the level of adrenocorticotropic hormone is reduced by at least about 50% after a period of administration of the pharmaceutical composition, wherein said reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (Item 362) 359. The pharmaceutical composition for use according to any one of items 288 to 358, wherein the level of adrenocorticotropic hormone is less than about 1.5 times the upper limit of normal after a period of administration of the pharmaceutical composition. (Item 363) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein the level of adrenocorticotropic hormone is within normal limits after a period of administration of said pharmaceutical composition. (Item 364) 364. The pharmaceutical composition for use according to any one of items 288 to 363, wherein the level of androstenedione is reduced by at least about 25% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (Item 365) 364. The pharmaceutical composition for use according to any one of items 288 to 363, wherein the level of androstenedione is reduced by at least about 30% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (Item 366) 364. The pharmaceutical composition for use according to any one of items 288 to 363, wherein the level of androstenedione is reduced by at least about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (Item 367) 364. The pharmaceutical composition for use according to any one of items 288 to 363, wherein the level of androstenedione is less than about 1.5 times the upper limit of normal after a period of administration of the pharmaceutical composition. (Item 368) 364. The pharmaceutical composition for use according to any one of items 288 to 363, wherein the level of androstenedione is within normal limits after a period of administration of said pharmaceutical composition. (Item 369) 369. The pharmaceutical composition for use according to any one of items 288 to 368, wherein the level of testosterone is reduced by at least about 25% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (Item 370) 369. The pharmaceutical composition for use according to any one of items 288 to 368, wherein the level of testosterone is reduced by at least about 30% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (Item 371) 369. The pharmaceutical composition for use according to any one of items 288 to 368, wherein the level of testosterone is reduced by at least about 50% after a period of administration of the pharmaceutical composition, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (Item 372) Item 373: The pharmaceutical composition for use according to any one of items 288 to 368, wherein the testosterone level is less than about 1.5 times the upper limit of normal after a period of administration of the pharmaceutical composition. 369. The pharmaceutical composition for use according to any one of items 288 to 368, wherein the level of testosterone is within normal limits after a period of administration of said pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof. (Item 374) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein after a period of administration of the pharmaceutical composition, the level of 17-hydroxyprogesterone is reduced by at least about 50%, and wherein the level of androstenedione is reduced by at least about 50%, and wherein the reduction in the levels of 17-hydroxyprogesterone and androstenedione is relative to the levels of 17-hydroxyprogesterone and androstenedione before administration of the pharmaceutical composition. (Item 375) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein after a period of administration of the pharmaceutical composition, the level of 17-hydroxyprogesterone is less than about 1.5 times the upper limit of normal and the level of androstenedione is less than about 1.5 times the upper limit of normal. (Item 376) 355. The pharmaceutical composition for use according to any one of items 288 to 354, wherein after a period of administration of said pharmaceutical composition the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits. (Item 377) 377. The pharmaceutical composition for use according to any one of items 334 to 376, wherein the subject exhibits a reduced glucocorticoid load after a period of administration of the pharmaceutical composition, wherein the reduced glucocorticoid load is relative to the glucocorticoid load before administration of the pharmaceutical composition. (Item 378) 378. The pharmaceutical composition for use according to item 377, wherein one or more symptoms of glucocorticoid burden selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, testicular adrenal quiescent tumor control, and fertility are improved after a period of administration of the pharmaceutical composition, and wherein the improvement in the one or more symptoms is an improvement relative to the state of the one or more symptoms before administration of the pharmaceutical composition. (Item 379) 379. The pharmaceutical composition for use according to any one of items 341 to 378, wherein the administration period is at least about 4 weeks. (Item 380) 379. The pharmaceutical composition for use according to any one of items 341 to 378, wherein the administration period is at least about 24 weeks. (Item 381) 379. The pharmaceutical composition for use according to any one of items 341 to 378, wherein the administration period is at least about 1 year. (Item 382) 382. The pharmaceutical composition for use according to any one of items 288 to 381, wherein the subject is a pediatric subject. (Item 383) 383. The pharmaceutical composition for use according to item 382, ​​wherein the pediatric subject is less than or equal to 6 years of age. (Item 384) 383. The pharmaceutical composition for use according to item 382, ​​wherein the pediatric subject is over 6 years old and under 11 years old. (Item 385) 383. The pharmaceutical composition for use according to item 382, ​​wherein the pediatric subject is over 10 years old and under 15 years old. (Item 386) 383. The pharmaceutical composition for use according to item 382, ​​wherein the pediatric subject is over 14 years of age and under 19 years of age. (Item 387) 382. The pharmaceutical composition for use according to any one of items 288 to 381, wherein the subject is an adult subject. (Item 388) 388. The pharmaceutical composition for use according to any one of items 387, wherein the adult subject is over 18 years of age. (Item 389) 389. The pharmaceutical composition for use according to any one of items 288 to 388, wherein the subject is a female. (Item 390) 389. The pharmaceutical composition for use according to any one of items 288 to 388, wherein the subject is male. (Item 391) 391. A pharmaceutical composition for use according to any one of items 288 to 390, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as the hydrochloride or p-toluenesulfonate salt. (Item 392) 391. A pharmaceutical composition for use according to any one of items 288 to 390, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a p-toluenesulfonate salt according to any one of items 228 to 238. (Item 393) 1. A compound, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in a method for treating congenital adrenal hyperplasia in a subject, wherein the compound is administered in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in the subject. (Item 394) 394. The compound according to item 393, wherein the decrease in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during the circadian release of one day before administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof with the level of the biomarker measured during the circadian release of one day after administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 395) The compound according to Item 394, wherein the circadian release occurs between 2:00 AM and 10:00 AM. 396. The compound of any one of items 393 to 395, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered 3 to 8 hours before the circadian release of the biomarker. (Item 397) 397. The compound according to any one of items 393 to 396, wherein the level of 17-hydroxyprogesterone is reduced by at least 25%. (Item 398) 70. The compound according to any one of items 393 to 396, wherein the level of 17-hydroxyprogesterone is reduced by at least 50%. (Item 399) 90. The compound according to any one of items 393 to 398, wherein the level of adrenocorticotropic hormone is reduced by at least 25%. (Item 400) 90. The compound according to any one of items 393 to 398, wherein the level of adrenocorticotropic hormone is reduced by at least 40%. (Item 401) 90. The compound according to any one of items 393 to 398, wherein the level of adrenocorticotropic hormone is reduced by at least 50%. (Item 402) 402. The compound according to any one of items 393 to 401, wherein the level of androstenedione is reduced by at least 25%. (Item 403) 402. The compound according to any one of items 393 to 401, wherein the level of androstenedione is reduced by at least 30%. (Item 404) 402. The compound according to any one of items 393 to 401, wherein the level of androstenedione is reduced by at least 50%. (Item 405) 402. The compound according to any one of items 393 to 401, wherein the level of 17-hydroxyprogesterone is reduced by at least 50% and the level of androstenedione is reduced by at least 50%. (Item 406) 406. The compound of any one of items 393 to 405, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once a day in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 407) 407. The compound of any one of items 393 to 406, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form. (Item 408) A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, for use in a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth dysfunction in a subject with classic congenital adrenal hyperplasia, wherein the compound is administered in an amount sufficient to reduce androstenedione levels in the subject. (Item 409) 409. The compound according to item 408, wherein said growth dysfunction is selected from one or more of accelerated height growth rate, accelerated weight gain rate or accelerated bone age. (Item 410) 409. The compound according to item 408 or 409, wherein the level of androstenedione is reduced by at least 25%. (Item 411) 409. The compound according to item 408 or 409, wherein the level of androstenedione is reduced by at least 30%. (Item 412) 409. The compound according to item 408 or 409, wherein the level of androstenedione is reduced by at least 50%. (Item 413) A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for use in a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia. (Item 414) 414. The compound according to item 413, wherein the one or more biomarkers of congenital adrenal hyperplasia are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 415) A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for use in a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia. (Item 416) 416. The compound according to item 415, wherein the corticosteroid is a glucocorticoid. (Item 417) 1. A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for use in a method for reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, wherein said side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, steroid hormone receptor agonist (SHR), ... a compound selected from: shing-like features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection. (Item 418) 418. The compound of any one of items 413 to 417, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% compared to the level before administration. (Item 419) 419. The compound of any one of items 413 to 418, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce androstenedione levels by at least 30% compared to pre-administration levels. (Item 420) 418. The compound of any one of items 413 to 417, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to (a) reduce 17-hydroxyprogesterone (17-OHP) levels by at least 50% compared to pre-administration levels, and (b) reduce androstenedione levels by at least 30% compared to pre-administration levels. (Item 421) 421. The compound of any one of items 413 to 420, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 422) 422. The compound of any one of items 413 to 421, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once a day in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 423) 423. The compound of any one of items 413 to 422, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in free base form. (Item 424) 1. A method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have an elevated level of the one or more biomarkers, administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. 1. A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for use in a method comprising: (Item 425) (iv) measuring the level of the one or more biomarkers in a biological sample obtained from the subject after administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof to determine whether the subject has a decreased level of the one or more biomarkers compared to the measurement in step (i). (Item 426) (v) If the subject has a decreased level of the one or more biomarkers, continuing the administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 427) The compound according to item 425 or 426, wherein steps (i) and (iv) are performed on biological samples taken from the subject in a similar manner and within the same time period of the day. (Item 428) 428. The compound of any one of items 425 to 427, wherein steps (i) and (iv) are performed on a biological sample taken from said subject within the time period of 2:00 AM to 10:00 AM of a day. (Item 429) 428. The compound of any one of items 425 to 427, wherein steps (i) and (iv) are performed on a biological sample taken from said subject within the daily time period of 6:00 AM to 10:00 AM. (Item 430) 429. The compound of any one of items 425 to 429, wherein steps (i) and (iv) comprise measuring the levels of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 431) 429. The compound of any one of items 425 to 429, wherein steps (i) and (iv) comprise measuring levels of (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione. (Item 432) 432. The compound according to any one of items 424 to 431, wherein step (i) comprises measuring the level of 17-hydroxyprogesterone (17-OHP), and the level of 17-hydroxyprogesterone (17-OHP) is elevated if it is greater than or equal to 1,000 ng / dL. (Item 433) 433. The compound of any one of items 424 to 432, wherein step (i) comprises measuring the level of androstenedione, and the level of androstenedione is elevated if it is higher than 200 ng / dL. (Item 434) 434. The compound of any one of items 424 to 433, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 435) 434. The compound of any one of items 424 to 433, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once a day in an amount equivalent to about 50 mg or about 100 mg of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine free base. (Item 436) 436. The compound of any one of items 424 to 435, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is administered in the free base form. (Item 437) 1. A compound which is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject, wherein the subject is in a fed state. (Item 438) 438. The compound according to item 437, wherein the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered to the subject together with a nutritional composition. (Item 439) 49. The compound according to item 438, wherein the nutritional composition is a liquid dietary supplement containing 1500 calories per liter with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrates. (Item 440) 439. The compound according to item 438 or 439, wherein the nutritional composition is administered in an amount of about 8 fluid ounces. (Item 441) 441. The compound of any one of items 438 to 440, wherein the nutritional composition is administered within 30 minutes of administering the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. (Item 442) 442. The compound according to any one of items 437 to 441, wherein administration of said 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof shows a positive food effect. (Item 443) C when the positive food effect compares oral administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in the fed and fasted states. max , AUC or a combination thereof. (Item 444) 444. The compound according to any one of items 437 to 443, wherein the ratio of AUC in the fed state to AUC in the fasted state is from about 5 to about 10. (Item 445) C in the fed state max C in the fasting state max444. The compound according to any one of items 437 to 443, wherein the ratio of [Brief explanation of the drawings]

[0116] [Figure 1] FIG. 1 is a graph showing the dissolution performance of several spray-dried dispersion formulations in 0.5 wt % simulated intestinal fluid (SIF) in phosphate buffered saline (PBS) (pH 6.5).

[0117] [Figure 2] FIG. 2 shows a vertical membrane flux cell integrated into the μDiss Profiler™ for use in membrane flux assays.

[0118] [Figure 3] 1 is a graph showing non-settling dissolution data for several spray-dried dispersion formulations and the compound of formula (I) in 0.5 wt % SIF in PBS (pH 6.5).

[0119] [Figure 4] Figure 4 is a graph showing membrane flux over time of 1 mg / mL GB / IB 0.5 wt% SIF dose of the compound of Formula (I) and various spray-dried dispersion formulations. The solid line shows flux (µg min-1cm-2) and the dotted line shows concentration (µg / mL) in 0.5% SIF.

[0120] [Figure 5-1] FIG. 5 is a flow diagram of the spray drying manufacturing process used to prepare 1000 g batches of SDD containing 25% compound of formula (I) and 75% PVP / VA64. [Figure 5-2] FIG. 5 is a flow diagram of the spray drying manufacturing process used to prepare 1000 g batches of SDD containing 25% compound of formula (I) and 75% PVP / VA64.

[0121] [Figure 6A]6A and 6B are line graphs showing the pharmacokinetic results of bioavailability and food effect studies in dogs. FIG. 6A shows the results from Cohort 1, and FIG. 6B shows the results from Cohort 2. [Figure 6B] 6A and 6B are line graphs showing the pharmacokinetic results of bioavailability and food effect studies in dogs. FIG. 6A shows the results from Cohort 1, and FIG. 6B shows the results from Cohort 2.

[0122] [Figure 7] FIG. 7 is a flow chart showing the study design for a Phase 1 study of the pharmacokinetics and food effect of the compound of formula (I) in healthy adult subjects.

[0123] [Figure 8A] 8A and 8B are line graphs showing the mean plasma concentration versus time profiles for the compound of formula (I) under fasted and fed states, respectively, in healthy adult subjects. [Figure 8B] 8A and 8B are line graphs showing the mean plasma concentration versus time profiles for the compound of formula (I) under fasted and fed states, respectively, in healthy adult subjects.

[0124] [Figure 9A] Figures 9A-9C are spaghetti plots of the pharmacokinetics of the compound of formula (I) in healthy adult subjects under fasting and fed conditions. Figure 9A shows the AUC0-tlast values. Figure 9B shows the AUC0-∞ values. Figure 9C shows the Cmax values. [Figure 9B] Figures 9A-9C are spaghetti plots of the pharmacokinetics of the compound of formula (I) in healthy adult subjects under fasting and fed conditions. Figure 9A shows the AUC0-tlast values. Figure 9B shows the AUC0-∞ values. Figure 9C shows the Cmax values. [Figure 9C]Figures 9A-9C are spaghetti plots of the pharmacokinetics of the compound of formula (I) in healthy adult subjects under fasting and fed conditions. Figure 9A shows the AUC0-tlast values. Figure 9B shows the AUC0-∞ values. Figure 9C shows the Cmax values.

[0125] [Figure 10] FIG. 10 is a flow chart showing the study design for a Phase 1 study of the bioavailability, pharmacokinetics and food effect of the compound of formula (I) in healthy adult subjects.

[0126] [Figure 11] FIG. 11 is a graph showing the study design for a Phase 2 study of the compound of formula (I) in adult subjects with congenital adrenal hyperplasia.

[0127] [Figure 12A] Figures 12A and 12B are graphs showing the arithmetic mean values ​​of adrenocorticotropic hormone (ACTH) (Figure 12A) and 17-hydroxyprogesterone (17-OHP) (Figure 12B) for all eight subjects in Cohort 1 plotted at each time point against pre-treatment baseline (circles), day 1 (squares), and day 14 (triangles). [Figure 12B] Figures 12A and 12B are graphs showing the arithmetic mean values ​​of adrenocorticotropic hormone (ACTH) (Figure 12A) and 17-hydroxyprogesterone (17-OHP) (Figure 12B) for all eight subjects in Cohort 1 plotted at each time point against pre-treatment baseline (circles), day 1 (squares), and day 14 (triangles).

[0128] [Figure 13A] Figures 13A and 13B are graphs showing the arithmetic mean values ​​of androstenedione (Figure 13A) and testosterone (Figure 13B) for all eight subjects in Cohort 1 plotted at each time point against pre-treatment baseline (circles), Day 1 (squares), and Day 14 (triangles). [Figure 13B]Figures 13A and 13B are graphs showing the arithmetic mean values ​​of androstenedione (Figure 13A) and testosterone (Figure 13B) for all eight subjects in Cohort 1 plotted at each time point against pre-treatment baseline (circles), Day 1 (squares), and Day 14 (triangles).

[0129] [Figure 14A] Figures 14A and 14B are graphs showing the decline in ACTH at 8, 10, and 12 hours post-dose. Figure 14A is a graph showing the values ​​for each time point compared to baseline. Figure 14B is a graph showing the average values ​​for all three time points. [Figure 14B] Figures 14A and 14B are graphs showing the decline in ACTH at 8, 10, and 12 hours post-dose. Figure 14A is a graph showing the values ​​for each time point compared to baseline. Figure 14B is a graph showing the average values ​​for all three time points.

[0130] [Figure 15A] Figures 15A and 15B are graphs showing the decrease in 17-OHP at 8, 10, and 12 hours after dosing. Figure 15A is a graph showing the values ​​for each time point compared to baseline. Figure 15B is a graph showing the average values ​​for all three time points. [Figure 15B] Figures 15A and 15B are graphs showing the decrease in 17-OHP at 8, 10, and 12 hours after dosing. Figure 15A is a graph showing the values ​​for each time point compared to baseline. Figure 15B is a graph showing the average values ​​for all three time points.

[0131] [Figure 16A] Figures 16A and 16B are graphs showing the decrease in androstenedione at 8, 10, and 12 hours post-dose. Figure 16A is a graph showing the values ​​for each time point compared to baseline. Figure 16B is a graph showing the average values ​​for all three time points. [Figure 16B]Figures 16A and 16B are graphs showing the decrease in androstenedione at 8, 10, and 12 hours post-dose. Figure 16A is a graph showing the values ​​for each time point compared to baseline. Figure 16B is a graph showing the average values ​​for all three time points.

[0132] [Figure 17A] Figure 17A is a graph showing mean plasma ACTH blood concentrations after a 50 mg dose of the compound of Formula (I) qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning time point. ACTH normal range: women 6-58 pg / mL; men 7-69 pg / mL.

[0133] [Figure 17B] Figure 17B is a graph showing the mean serum 17-OHP blood concentration after a 50 mg dose of the compound of formula (I) qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning time point. 17-OHP normal range: women <207 ng / dL; men <139 ng / dL.

[0134] [Figure 17C] Figure 17C is a graph showing mean serum androstenedione blood concentrations after a 50 mg dose of the compound of Formula (I) qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning time point. Androstenedione normal range: women 26-214 ng / mL; men 33-134 ng / mL.

[0135] [Figure 18A] Figure 18A is a graph showing mean plasma ACTH blood concentrations after a 100 mg dose of the compound of Formula (I) qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning time point. ACTH normal range: women 6-58 pg / mL; men 7-69 pg / mL.

[0136] [Figure 18B]Figure 18B is a graph showing the mean serum 17-OHP blood concentration after a 100 mg dose of the compound of formula (I) qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning time point. 17-OHP normal range: women <207 ng / dL; men <139 ng / dL.

[0137] [Figure 18C] Figure 18C is a graph showing mean serum androstenedione blood concentrations after a 100 mg dose of compound of Formula (I) qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning time point. Androstenedione normal range: women 26-214 ng / mL; men 33-134 ng / mL.

[0138] [Figure 19A] Figure 19A is a graph showing mean plasma ACTH blood concentrations after a 100 mg dose of a compound of formula (I) with dinner (Cohort 3). Error bars represent the standard error of the mean for each morning time point. ACTH normal range: women 6-58 pg / mL; men 7-69 pg / mL.

[0139] [Figure 19B] Figure 19B is a graph showing the mean serum 17-OHP blood concentration after a 100 mg dose of the compound of formula (I) with dinner (Cohort 3). Error bars represent the standard error of the mean for each morning time point. 17-OHP normal range: women < 207 ng / dL; men < 139 ng / dL.

[0140] [Figure 19C] Figure 19C is a graph showing the mean serum androstenedione blood concentrations after a 100 mg dose of a compound of formula (I) with dinner (Cohort 3). Error bars represent the standard error of the mean for each morning time point. Androstenedione normal range: women 26-214 ng / mL; men 33-134 ng / mL.

[0141] [Figure 20]FIG. 20 is a scheme illustrating a manufacturing process for forming a 50 mg capsule of a compound of formula (I).

[0142] [Figure 21] FIG. 21 is an alternative scheme showing a manufacturing process for forming a 50 mg capsule of a compound of formula (I).

[0143] [Figure 22A] 22A and 22B are schemes illustrating the manufacturing process for forming SDD granules of the compound of formula (I). [Figure 22B] 22A and 22B are schemes illustrating the manufacturing process for forming SDD granules of the compound of formula (I).

[0144] [Figure 23] FIG. 23 is a scheme illustrating the manufacturing process for forming a 50 mg / nL liquid formulation 1 of the compound of formula (I).

[0145] [Figure 24] FIG. 24 is a scheme illustrating the manufacturing process for forming a 50 mg / nL liquid formulation 2 of the compound of formula (I).

[0146] [Figure 25] FIG. 25 is an XRPD spectrum of crystalline Form I of the free base of the compound of formula (I).

[0147] [Figure 26] FIG. 26 is a DSC spectrum of crystalline Form I of the free base of the compound of formula (I).

[0148] [Figure 27] FIG. 27 is an XRPD spectrum of crystalline Form 1 of the tosylate salt of the compound of formula (I).

[0149] [Figure 28] FIG. 28 is a DSC and TGA spectrum of crystalline Form 1 of the tosylate salt of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0150] As described herein, the compound of formula (I): [ka] 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or its pharmaceutically acceptable salt is a selective CRF1 receptor antagonist, which has been found to be effective in treating congenital adrenal hyperplasia.Specifically, the compound of formula (I) has been found to selectively reduce some biomarkers associated with congenital adrenal hyperplasia.

[0151] Newborn screening for CAH is performed by immunoassay, measuring 17-OHP levels in heelstick capillary blood samples obtained within the first 72 hours of life. Blood samples are analyzed for 17-OHP by a commercially available dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA; PerkinElmer, Waltham Massachusetts) (White et al., J. Pediatr. 163:10-12 (2013)). Nine states in the United States use a secondary screening test, utilizing biochemical and molecular genetic testing methods, administered between 8 and 14 days of life, and five states strongly recommend it. Biochemical methods include immunoassays using organic solvent extraction or liquid chromatography followed by tandem mass spectrometry to measure steroid ratios of 17-OHP, androstenedione, and 21-deoxycortisol to cortisol (see, e.g., Speiser et al., Int. J. Pediatr. Endocrinol. 2010:494173, 2010). Genetic screening searches for CYP21A2 mutations associated with CAH. The addition of a second screening method, while not widely used in the United States, can potentially improve the sensitivity of the overall screening process; in this case, the sensitivity of the first screen alone is approximately 72%.

[0152] In the absence of results from newborn screening, girls with classic CAH are usually identified because of the presence of ambiguous genitalia. Males have normal genitalia at birth, and therefore the diagnosis is not made unless newborn screening is performed or other medical complications are noted. Infants who are not initially diagnosed with CAH and who suffer from the salt-wasting form of the disease are later diagnosed with poor weight gain, vomiting, hyperkalemia, and hyponatremia within the first few weeks of life.

[0153] Treatment of CAH, from infancy to adulthood, is based on normalizing hormone and steroid levels from diagnosis using a variety of medications. Glucocorticoids are the current standard of care for CAH, used both to correct endogenous cortisol deficiency and to reduce elevated pituitary ACTH levels, which drive increased androgen production. Unlike treatment for Addison's disease (adrenal insufficiency), in which cortisol replacement is insufficient, treatment for CAH must also reduce ACTH production to control subsequent androgen excess. Therefore, the goals of glucocorticoid treatment include cortisol replacement and ACTH suppression to prevent virilization and menstrual disorders in women and to inhibit testicular adrenal rest tumors in men. Mineralocorticoid replacement is necessary in such patients with the salt-wasting form of CAH to achieve normal plasma renin activity for maintaining normal blood pressure, electrolyte balance, and volume status.

[0154] Glucocorticoid treatment regimens must support normal physiology and also ensure that sufficient cortisol is available during events that may provoke a strong stress response (e.g., intercurrent illness, exercise, hypotension). Careful monitoring is also necessary to avoid the development of iatrogenic Cushing's syndrome due to glucocorticoid overtreatment or Addison's syndrome due to inadequate treatment in an effort to adequately suppress androgen production.

[0155] Overtreatment with mineralocorticoids can cause hypertension, while undertreatment can result in hypotension, salt wasting, fatigue, and increased glucocorticoid requirements. Typical laboratory tests to monitor treatment effectiveness include measurement of plasma concentrations of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes.

[0156] Adult patients with CAH have an increased prevalence of cardiovascular disease risk factors, including obesity, hypertension, and insulin resistance (see, e.g., Kim et al., Semin. Reprod. Med. 27(4):316-21 (2009)). Studies of large cohorts (n=244) of pediatric and adult CAH patients demonstrated that patients prescribed various glucocorticoid treatment regimens often still suffered from poor hormonal control and the adverse outcomes described above (see, e.g., Finkielstain et al., J. Clin. Endocrinol Metab. 97(12):4429-38 (2012).

[0157] Treatment of CAH involves efforts to normalize cortisol deficiency with glucocorticoids (usually hydrocortisone in children, but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults) and, when needed for the salt-wasting form, with mineralocorticoids (usually fludrocortisone). However, the glucocorticoid doses required to achieve adequate suppression of androgen excess usually well exceed the normal physiologic doses used for cortisol replacement alone, as in patients with Addison's disease. Increased exposure to glucocorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, and decreased bone mineral density in patients with CAH (e.g., Elnecave et al., J. Pediatr. Endocrinol. Metab. 21:1155-62 (2008); King et al., J. Clin. Endocrinol. Metab. 91(3):8656-59 (2006); Migeon et al., Endocrinol. Metab. Clin. North Am. 30:193-206 (2001). Recently, best practices for the clinical management of congenital adrenal hyperplasia were published in the Journal of Clinical Endocrinology and Metabolism (Speiser, PW, et al. J. Clin. Endocrinol. Metab. November 2018, 103(11): 1-46), which is incorporated by reference in its entirety.

[0158] Corticotropin-releasing factor (CRF) was isolated from sheep hypothalamus and identified as a 41-amino acid peptide. CRF has been found to cause significant alterations in endocrine, neurological, and immune system functions. CRF is believed to be the primary physiological regulator of the basal and stress-induced release of adrenocorticotropic hormone ("ACTH"), β-endorphin, and other pro-opiomelanocortin ("POMC")-derived peptides from the anterior pituitary gland (see, e.g., Vale et al., Science 213:1394-1397, 1981). CRF secretion triggers the release of ACTH from corticotrophs in the anterior pituitary gland via binding to the CRF1 receptor, a member of the class B family of G-protein-coupled receptors.

[0159] Due to the physiological importance of CRF, the development of biologically active small molecules with significant CRF1 receptor binding activity that are capable of antagonizing the CRF1 receptor remains a desirable goal and has been the subject of ongoing research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and substance abuse.

[0160] The pituitary hormone ACTH, under the control of hypothalamic corticotropin-releasing factor (CRF), stimulates cholesterol uptake in the adrenal glands, driving the synthesis of pregnenolone, which initiates steroidogenesis. The adrenal cortex consists of three regions, each producing distinct classes of hormones, many of which are driven by ACTH mobilization of cholesterol through this pathway. Deficiency of these enzymes as a result of mutation or deletion results in increased substrate concentrations. In the most common form of CAH, caused by mutation or deletion in the 21-hydroxylase gene (CYP21A2), potent androgens are produced by the adrenal glands due to accumulation of the steroid precursors progesterone and 17-hydroxyprogesterone (17-OHP). Plasma levels of 17-OHP can reach 10 to 1,000 times normal concentrations in these cases. These increases result in the overproduction of androgens, specifically androstenedione, testosterone, and dihydroxytestosterone, which causes virilization in women. Furthermore, 21-hydroxylase deficiency in CAH leads to insufficient biosynthesis of glucocorticoids and mineralocorticoids, specifically cortisol and aldosterone. Cortisol is a critical negative feedback regulator of hypothalamic CRF secretion and pituitary ACTH release. Lack of glucocorticoid synthesis and release eliminates inhibition on the hypothalamus and pituitary, thereby increasing ACTH levels. Excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis, resulting in adrenal hyperplasia.

[0161] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are described herein for use in this disclosure.Other suitable methods and materials known in the art can also be used.Materials, methods and examples are merely illustrative and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety.In case of conflict, the present specification (including definitions) shall prevail.

[0162] Reported as degrees Celsius, DSC, TGA or T g The term "about" preceding a value for has an acceptable variation of ±5° C. In all other instances, unless otherwise specified, the term "about" preceding a stated value includes the stated value, and also includes ±20% of the stated value, and more particularly includes values ​​of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0163] To provide a more precise description, some of the quantitative expressions herein are recited as a range of about amount X to about amount Y. When a range is recited, it is understood that the range is not limited to the recited upper and lower limits, but rather includes the entire range from about amount X to about amount Y, or any range therein.

[0164] "Room temperature" or "room temperature (RT)" refers to the ambient temperature of a typical laboratory, which is typically about 25°C.

[0165] "Spray drying" refers to a method of producing a dry powder from a solution or slurry. The solution or slurry is atomized or rapidly dried using a hot gas, such as air or nitrogen, which causes the solvent to evaporate quickly and uniformly. "Spray-dried dispersion" refers to the powder resulting from the spray-drying process.

[0166] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all biologically or otherwise undesirable solvents, cosolvents, complexing agents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is contemplated for use in therapeutic formulations except insofar as it is incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the formulation. In addition, various excipients, such as those commonly used in the art, may be included. These and other such compounds are described in literature, for example, in The Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0167] "Subject," as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, and any other vertebrate or invertebrate. In some embodiments, the subject is a human.

[0168] In some embodiments, the subject experiences and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has clinical records indicating that the subject has CAH (and, optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.

[0169] The term "pediatric subject," as used herein, refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including: neonates (birth to the first month of life); infants (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years, including but not limited to, up to their 22nd birthday). Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (including but not limited to, up to their 22nd birthday). In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days to less than 1 year of age, from 1 month to less than 4 months of age, from 3 months to less than 7 months of age, from 6 months to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[0170] As used herein, the term "treat" or "treatment" refers to a curative or palliative measure. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, a stabilized (i.e., not worsening) state of the disease, a delay or slowing of disease progression, an improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0171] The term "preventing," as used herein, means preventing, in whole or in part, the occurrence, recurrence, or spread of a disease or condition described herein, or a symptom thereof.

[0172] The term "administration" or "administering" refers to a method of providing a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The preferred method of administration can vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0173] As used herein, a "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I), sufficient to achieve a desired effect, which may vary depending on the nature and severity of the disease state and the efficacy of the compound. A therapeutic effect is some degree of alleviation of one or more symptoms of a disease, and may include a cure of the disease. "Cure" means that the symptoms of active disease have disappeared. However, some long-term or permanent effects of the disease may exist even after a cure has been achieved (e.g., extensive tissue damage, etc.).

[0174] The term "amorphous" refers to a solid in a non-crystalline solid state. An amorphous solid is a disordered arrangement of molecules and therefore does not have a distinguishable crystal lattice or unit cell, and consequently, no definable long-range order. The solid-state form of a solid can be determined by polarized optical microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those skilled in the art.

[0175] As used herein, "time of a time period of a day" refers to a period defined by the start time of a time period and the end time of a time period.All these times refer to the local time when the sample is collected.The phrase "same time period of a day" means that when referring to the sample collected from a subject, for example, the sample collected at 8:15 AM and the sample collected at 9:15 AM are considered to be collected at the same time period of a day, for example, 2 AM to 10 AM or 6 AM to 10 AM.

[0176] method The present disclosure relates to a method for treating congenital adrenal hyperplasia (CAH). The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of an SDD of the present disclosure, the SDD comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure, the SDD comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0177] Provided herein are methods for treating congenital adrenal hyperplasia (CAH), comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to normalize or partially normalize levels of biomarkers associated with congenital adrenal hyperplasia. In some embodiments, normalizing or partially normalizing levels of biomarkers comprises reducing elevated levels of biomarkers or improving depressed levels of biomarkers compared to subjects without CAH.

[0178] Provided herein is a method for treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of one or more biomarkers associated with congenital adrenal hyperplasia. In some embodiments, the biomarkers are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in the subject.

[0179] In some embodiments, the decrease in the level of any of the biomarkers (e.g., any of 17-OHP, ACTH, and androstenedione) is determined by comparing the level of the biomarker measured during circadian release on a day before administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof with the level of the biomarker measured during circadian release on a day after administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof. The day before administering the compound of Formula (I) refers to a subject who has not yet received the compound of Formula (I) within at least the past 24 hours.

[0180] In some embodiments, the circadian release of biomarkers associated with CAH occurs between 2:00 AM and 10:00 AM. In other embodiments, the circadian release of biomarkers associated with CAH occurs between 6:00 AM and 10:00 AM.

[0181] In some embodiments of any of the methods disclosed herein, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at night or before sleep (i.e., bedtime administration). In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered 3 to 8 hours before the circadian release of the biomarker. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered 6 to 8 hours before the circadian release of the biomarker. Administration before the circadian release may be applicable to shift workers (e.g., those who work at night and sleep during the day), in which case administration is not necessarily at night. Thus, administration depends on the expected circadian release of the biomarker and may vary depending on the particular work and sleep patterns of the individual (i.e., subject, patient).

[0182] In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from pre-administration levels. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 25%. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 50%. In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by an amount from pre-administration levels of about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 50% to about 90%, about 55% to about 90%, or about 60% to about 90%.

[0183] In some embodiments, the level of 17-hydroxyprogesterone is reduced to a level within the range of 17-hydroxyprogesterone expected for a subject without CAH, i.e., less than 1,000 ng / dL, or less than 200 ng / dL.

[0184] In some embodiments of the methods provided herein, the level of adrenocorticotropic hormone is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from the pre-administration level. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 25%. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 40%. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 50%.

[0185] In some embodiments of the methods provided herein, the level of adrenocorticotropic hormone is reduced by an amount of about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 50% to about 90%, about 55% to about 90%, or about 60% to about 90% from the pre-administration level.

[0186] In some embodiments, the adrenocorticotropic hormone level is reduced to a level within the range of adrenocorticotropic hormone expected for a subject without CAH.

[0187] In some embodiments of the methods provided herein, androstenedione levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from pre-administration levels.In some embodiments, androstenedione levels are reduced by at least 25%.In some embodiments, androstenedione levels are reduced by at least 30%.In some embodiments, androstenedione levels are reduced by at least 50%.

[0188] In some embodiments of the methods provided herein, androstenedione levels are reduced by an amount from pre-administration levels of about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 50% to about 90%, about 55% to about 90%, or about 60% to about 90%.

[0189] In some embodiments, androstenedione levels are reduced to a level within the range of androstenedione expected for a subject without CAH, i.e., below 200 ng / dL.

[0190] Similarly, provided herein is a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and impaired growth in a subject with classic congenital adrenal hyperplasia, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce one or more biomarkers of CAH in the subject, for example, to reduce androstenedione in the subject. Impaired growth can refer to, for example, accelerated height growth rate, accelerated weight gain rate, and / or accelerated bone age.

[0191] Provided herein is a method for reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject with congenital adrenal hyperplasia, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more biomarkers of congenital adrenal hyperplasia are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0192] Provided herein is a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is a glucocorticoid.

[0193] Provided herein is a method for reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof. The long-term effects of glucocorticoid treatment are well documented in the art (e.g., Oray, (See M. et al. (2016): Long-term effect of glucocorticoids, Expert Opinion on Drug Safety. DOI: 10.1517 / 14740338.2016.1140743.) Such side effects may affect any biological system, for example, musculoskeletal (e.g., osteoporosis, avascular necrosis of bone and myopathy), endocrine and metabolic (e.g., hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal suppression), gastrointestinal (e.g., gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis), cardiovascular (e.g., hypertension, coronary heart disease, ischemic heart disease, heart failure), dermatological (e.g., dermatoporosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism and alopecia), neuropathological (e.g., mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia and delirium), ophthalmologic (e.g., cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections and central serous chorioretinopathy) and immunologic (e.g., suppression of cell-mediated immunity, predisposition to infection and reactivation of latent infection).

[0194] Thus, in some embodiments, the side effects of glucocorticoid treatment are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, elation, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, reactivation of latent infection, and any combination thereof.

[0195] 1. A method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione in a biological sample obtained from the subject; (ii) analyzing the level of one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy subject without congenital adrenal hyperplasia; and (iii) if the subject is determined to have elevated levels of one or more biomarkers, administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the method further comprises the step of (iv) measuring the level of one or more biomarkers in a biological sample obtained from the subject after administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to determine whether the subject has a decreased level of the one or more biomarkers compared to the measurements of step (i). In some embodiments, the method further comprises the step of (v) continuing to administer the compound of Formula (I) or a pharmaceutically acceptable salt thereof if the subject has a decreased level of the one or more biomarkers.

[0197] In some embodiments, steps (i) and (iv) are performed in a similar manner and during the same time period of a day on biological samples collected from a subject. In some embodiments, steps (i) and (iv) are performed during the time period of the day from 2:00 AM to 10:00 AM on biological samples collected from a subject. In some embodiments, steps (i) and (iv) are performed during the time period of the day from 6:00 AM to 10:00 AM on biological samples collected from a subject.

[0198] In some embodiments, steps (i) and (iv) comprise measuring the levels of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0199] In some embodiments, steps (i) and (iv) comprise measuring levels of (a) 17-hydroxyprogesterone (17-OHP), (b) adrenocorticotropic hormone (ACTH), and (c) androstenedione.

[0200] In some embodiments, step (i) includes measuring the level of 17-hydroxyprogesterone (17-OHP), and the level of 17-hydroxyprogesterone (17-OHP) is elevated if it is greater than or equal to 1,000 ng / dL.

[0201] In some embodiments, step (i) comprises measuring the level of androstenedione, and determining that the level of androstenedione is elevated if it is greater than 200 ng / dL.

[0202] In some embodiments of the disclosed methods, the compound of Formula (I) is administered in an amount equivalent to about 25 mg to about 150 mg of the free base of the compound of Formula (I). In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 50 mg or about 100 mg of the free base of the compound of Formula (I).

[0203] In some embodiments of the methods disclosed herein, the compound of formula (I) is administered in free base form.

[0204] In some embodiments of the methods disclosed herein, the compound of formula (I) is administered once daily.

[0205] Also provided herein are methods for treating CAH in a pediatric subject. The methods include administering to the pediatric subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include administering to the pediatric subject a therapeutically effective amount of an SDD of the present disclosure, the SDD comprising a polymer and a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include administering to the pediatric subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure containing an SDD comprising a polymer and a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pediatric subject is a newborn. In some embodiments, the pediatric subject is an infant. In some embodiments, the pediatric subject is a child. In some embodiments, the pediatric subject is an adolescent.

[0206] In some embodiments of the disclosed methods, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state. The term "fed state," as used herein, refers to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof from about 1 hour before consuming food or a nutritional composition to about 1 hour after consuming the food or nutritional composition. The term "fasted state," as used herein, refers to a gap of at least 2 hours between consuming food or a nutritional composition and administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject together with food or a nutritional composition, such as a nutritional supplement or formula, a meal replacement drink, a liquid meal supplement, or a high-calorie liquid meal. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject within about 1 hour before the subject consumes food or a nutritional composition. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject within about 1 hour after the subject consumes food or a nutritional composition. Examples of suitable nutritional compositions include, but are not limited to, infant formula, dietary supplements, meal replacements, and hydration compositions. In some embodiments, the food is a product containing concentrated calories and protein. In some embodiments, the nutritional composition is a composition used for enteral and parenteral support for infants, infant formula, supplements for the elderly, and supplements for people with gastrointestinal difficulties and / or malabsorption. Adult and pediatric nutritional formulas are well known in the art and are commercially available (e.g., Similac®, Ensure®, Jevity®, and Alimentum®, Ross Products Division, Abbott Laboratories, Columbus, Ohio).

[0207] In some embodiments, the nutritional composition is in liquid form. The energy density of the nutritional composition, when in liquid form, can range from about 0.6 Kcal to about 3 Kcal per mL. In some embodiments, the nutritional composition is in solid or powder form. When in solid or powder form, the nutritional supplement can contain about 1.2 to more than 9 Kcal per gram, such as about 3 to 7 Kcal per gram.

[0208] In some embodiments, the nutritional composition is a meal replacement bar. Examples include PowerBar®, Glucerna® bar, Choice DM® bar, Ensure® bar, and Boost® bar. In some embodiments, the nutritional composition is a nutritional shake or meal replacement drink. Commercial examples include Ensure® brand adult products (such as Ensure® Original, Ensure® Plus, Ensure® Enlive, Ensure® High Protein, Ensure® Clear, and Ensure® Light), Glucerna®, Choice DM®, Slim Fast®, Pediasure®, Glytrol®, and Resource®. In some embodiments, the nutritional composition is Ensure® Plus. In some embodiments, the nutritional composition is vanilla flavored Ensure® Plus. Ensure Plus® is a high-calorie liquid dietary supplement containing 1500 calories per liter with a calorie distribution of 14.7% protein, 32% fat and 53.3% carbohydrates.

[0209] In some embodiments of the disclosed methods, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject with 8 fluid ounces (237 mL) of Ensure® Plus. In some embodiments, the Ensure® Plus is vanilla flavored.

[0210] In some embodiments of this method, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject after the administration of the nutritional composition.In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject before the administration of the nutritional composition.In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject simultaneously with the administration of the nutritional composition.

[0211] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, followed by the administration of a nutritional composition. In some embodiments, the nutritional composition is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 60 minutes after the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or within a range defined by any of the above values. In some embodiments, the nutritional composition is administered 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, or 60 minutes after the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or within a range defined by any of the above values. In some embodiments, the nutritional composition is administered within 30 minutes after the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the disclosed methods, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject with 8 fluid ounces (237 mL) of Ensure® Plus. In some embodiments, the Ensure® Plus is vanilla flavored.

[0212] In some embodiments, the nutritional composition is administered to a subject, followed by administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 60 minutes after administration of the nutritional composition, or within a range defined by any of the preceding values. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, or 60 minutes after administration of the nutritional composition, or within a range defined by any of the preceding values. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered within 30 minutes after administration of the nutritional composition. In some embodiments of the disclosed methods, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject with 8 fluid ounces (237 mL) of Ensure® Plus. In some embodiments, the Ensure® Plus is vanilla flavored.

[0213] In some embodiments of the method, a food effect is observed during administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the fed and fasted states. The term "food effect," as used herein, refers to a decrease in the AUC (area under the curve, AUC) of an active agent when a compound of Formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject with a meal or in the fed state, compared to the same value when the same compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in the fasted state. (0-t) and / or AUC (0-∞) ) or C max The food effect (F) is calculated as follows: F%=[(X 絶食 -X 摂食 ) / X 絶食 ] x 100 (In the formula, X 摂食 and X 絶食are the AUC(AUC (0-t) and / or AUC (0-∞) ) or C max In some embodiments, an increased or positive food effect is observed when a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state. In some embodiments, administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof increases or positively affects the food effect, such that C is increased when orally administered in a fed state compared to a fasted state. max and / or an increase in AUC is observed.

[0214] In some embodiments of the method, the ratio of AUC in the fed state to AUC in the fasted state is about 5 to about 10, such as about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 8 to about 10. In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is about 5, about 6, about 7, about 8, about 9, or about 10, or within a range defined by any of the foregoing values. In some embodiments of the method, the ratio of AUC in the fed state to AUC in the fasted state is about 10 to about 20.

[0215] In some embodiments of the method, the ratio of AUC in the fed state to AUC in the fasted state is 5 to 10, such as 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 6 to 8, 6 to 7, 7 to 10, 7 to 9, 7 to 8, 8 to 10, 8 to 9, or 8 to 10. In some embodiments, the ratio of AUC in the fed state to AUC in the fasted state is 5, 6, 7, 8, 9, or 10, or within a range defined by any of the foregoing values.

[0216] In some embodiments of the method, C in the fed state max C in the fasting state maxto about 5 to about 10, such as about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 8 to about 10. max C in the fasting state max In some embodiments, the average C of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 5, about 6, about 7, about 8, about 9, or about 10, or within a range defined by any of the foregoing values. max is about 1.5 to about 3 times higher in the fed state compared to the fasted state. In some embodiments of the method, C in the fed state max C in the fasting state max to is 5-10, such as 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 8-10. max C in the fasting state max In some embodiments, the ratio of the average C of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the average C of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 5, 6, 7, 8, 9, or 10, or within a range defined by any of the foregoing values. max is 1.5 to 3 times higher in the fed state compared to the fasted state. In some embodiments, the mean C max is about two times higher in the fed state compared to the fasted state. In some embodiments of the method, C in the fed state max C in the fasting state max The ratio to is about 10 to about 20.

[0217] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered to a subject with a meal. In some embodiments, the meal is a high-fat, high-calorie meal. In some embodiments, the meal is a low-fat, low-calorie meal. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered within about 5 minutes after starting the meal. In some embodiments, the meal is dinner. In some embodiments, the meal is breakfast.

[0218] In some embodiments, the fed state is with a high-fat meal. In some embodiments, the fed state is with a low-fat meal. The FDA has proposed guidance on high-fat and low-fat meals ("Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations Guidance for Industry," US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), February 2019, Clinical Pharmacology). Table 1 shows the test meal definitions provided by the FDA guidance. [Table 1]

[0219] The composition of the high-fat diet suggested by the FDA guidance is shown in Table 2. [Table 2]

[0220] The composition of the low-fat diet suggested by FDA guidance is shown in Table 3. [Table 3]

[0221] In some embodiments, the high-fat diet contains 800-1000 Kcal total and 500-600 Kcal fat, hi some embodiments, the low-fat diet contains 400-500 Kcal total and 100-125 Kcal fat.

[0222] Also provided herein is a method for improving the gastrointestinal absorption of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a subject. The method comprises orally administering to the subject a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof that is not prepared as a spray-dried dispersion. In some embodiments, the subject is a pediatric subject.

[0223] Similarly, provided herein is a method for improving the oral bioavailability of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a subject, the method comprising orally administering to the subject a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof that is not prepared as a spray-dried dispersion.

[0224] In some embodiments of the methods provided herein, the subject is a pediatric subject.

[0225] Also provided herein is a method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a lipid-based semi-solid formulation. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is administered to a subject in a fed state.

[0226] Also provided herein is a pharmaceutical composition of the present disclosure for use in a method for treating congenital adrenal hyperplasia (CAH) in a subject. In some embodiments, the subject is in a fed state.

[0227] In some embodiments, the pharmaceutical composition is administered to a subject along with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement containing about 1,000 to about 2,000 calories per liter with a fat content greater than about 30%. In some embodiments, the nutritional composition is a liquid dietary supplement containing 1,500 calories per liter with a calorie distribution of 14.7% protein, 32% fat, and 53.3% carbohydrates. In some embodiments, the nutritional composition is administered in an amount of about 6 to about 12 fluid ounces. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the pharmaceutical composition.

[0228] In some embodiments, the pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is determined by comparing the C of a compound of Formula (I) when the pharmaceutical composition is administered orally in the fed and fasted states. max , AUC, or a combination thereof. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 5 to about 10. In some embodiments, the C of the compound of Formula (I) in the fed state is measured in terms of max C of the compound of formula (I) in the fasting statemax In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 5 to about 10. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 10 to about 20. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4 or 5 to 10. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4. max C of the compound of formula (I) in the fasting state maxIn some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1.5 to 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1.5 to 3. max C of the compound of formula (I) in the fasting state max The ratio to is 1.5 to 3.

[0229] In some embodiments, the subject is a pediatric subject.

[0230] In some embodiments, the pharmaceutical composition is formulated for oral administration and exhibits a positive food effect when administered orally. In some embodiments, the compound of formula (I) has a fed state AUC to fasted state AUC ratio of about 5 to about 10. In some embodiments, the compound of formula (I) has a fed state C max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 10 to about 20. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 10 to about 20. max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4 or about 5 to about 10. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4 or about 5 to about 10. max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4. max C in the fasting state maxIn some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1.5 to about 3. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1.5 to about 3. max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of 1 to 4 or 5 to 10. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of 1 to 4 or 5 to 10. max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state that is 1 to 4. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state that is 1 to 4. max C in the fasting state max In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of 1.5 to 3. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of 1.5 to 3. max C in the fasting state max has a ratio to

[0231] In some embodiments, the pharmaceutical composition is administered to a subject with a meal. In some embodiments, the meal is a high-fat meal. In some embodiments, the meal is a low-fat meal. In some embodiments, the pharmaceutical composition is administered within about 5 minutes after starting the meal. In some embodiments, the meal is dinner. In some embodiments, the meal is breakfast.

[0232] In some embodiments, administration of the pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is a decrease in the C of the compound of formula (I) when comparing oral administration of the pharmaceutical composition in the fed and fasted states. max, AUC, or a combination thereof. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 5 to about 10. In some embodiments, the C of the compound of Formula (I) in the fed state is measured in terms of max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 5 to about 10. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 10 to about 20. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1 to about 4. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is about 1.5 to about 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4 or 5 to 10. max C of the compound of formula (I) in the fasting state maxIn some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1 to 4. max C of the compound of formula (I) in the fasting state max In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1.5 to 3. In some embodiments, the ratio of the AUC of the compound of Formula (I) in the fed state to the AUC of the compound of Formula (I) in the fasted state is 1.5 to 3. max C of the compound of formula (I) in the fasting state max The ratio to is 1.5 to 3.

[0233] For the avoidance of doubt, there is also provided herein a corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the corresponding methods described herein.

[0234] For the avoidance of doubt, there is also provided herein the use of a corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the corresponding methods described herein.

[0235] For the avoidance of doubt, there is also provided herein the use of a corresponding pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the corresponding methods described herein.

[0236] Glucocorticoid load, decreased adrenal androgens and precursors Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to glucocorticoid receptors, which are present in almost all vertebrate cells. In some embodiments, the subject is concurrently receiving a dose of glucocorticoid. In some embodiments, the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate. In some embodiments, the glucocorticoid is cortisol (hydrocortisone). In some embodiments, the glucocorticoid is cortisone. In some embodiments, the glucocorticoid is prednisone. In some embodiments, the glucocorticoid is dexamethasone.

[0237] In some embodiments, the glucocorticoid dosage is measured in hydrocortisone equivalents. In some embodiments, the glucocorticoid dosage is measured as a multiple of the upper normal limit of physiological dosing in hydrocortisone equivalents. Any glucocorticoid can be administered at a dose that achieves approximately the same glucocorticoid effect as normal cortisol production. This is referred to as physiological replacement or maintenance dosing.

[0238] In some embodiments, the glucocorticoid dose is a physiological dose measured after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is about 4 to about 12 mg / m2 measured after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 In some embodiments, the glucocorticoid dose is about 4 to about 9 mg / m2, measured after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 In some embodiments, the glucocorticoid dose is a physiological dose of about 8 mg / m2 / day, measured after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.2 The physiological dose is less than 100 mg / day.

[0239] In some embodiments, the glucocorticoid dose is a physiological dose measured after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is about 4 to about 12 mg / m2 measured after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 In some embodiments, the glucocorticoid dose is from about 4 to about 9 mg / m2, measured after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 In some embodiments, the glucocorticoid dose is about 8 mg / m2 measured after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 This is a physiological dose of less than 100 mg / day.

[0240] In some embodiments, the glucocorticoid dose concurrently administered to the subject is a physiologically normal dose in hydrocortisone equivalents. In some embodiments, the glucocorticoid dose concurrently administered to the subject is determined after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose concurrently administered to the subject is determined after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the physiologically normal dose in hydrocortisone equivalents is about 2 to about 16 mg / m 2 In some embodiments, the physiologically normal dose in hydrocortisone equivalents is about 4 to about 12 mg / m 2 In some embodiments, the normal physiological dose in hydrocortisone equivalents is about 5 to about 11 mg / m 2 In some embodiments, the physiologically normal dose in hydrocortisone equivalents is about 6 to about 10 mg / m 2 In some embodiments, the normal physiological dose in hydrocortisone equivalents is about 7 to about 9 mg / m2 In some embodiments, the physiologically normal dose in hydrocortisone equivalents is about 4 to about 9 mg / m 2 In some embodiments, the normal physiological dose in hydrocortisone equivalents is about 8 mg / m 2 In some embodiments, the normal physiological dose in hydrocortisone equivalents is about 12 mg / m 2 In some embodiments, the normal physiological dose in hydrocortisone equivalents is about 8 mg / m 2 In some embodiments, the physiologically normal dose in hydrocortisone equivalents is less than about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16 mg / m 2 / day, or within a range defined by any of the preceding values.

[0241] In some embodiments, the glucocorticoid dose administered to the subject simultaneously is the upper normal limit of the normal physiological dose in hydrocortisone equivalents. In some embodiments, the glucocorticoid dose administered to the subject simultaneously is determined after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose administered to the subject simultaneously is determined after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the upper normal limit is 1.5 times the normal physiological dose. In some embodiments, the upper normal limit is about 1.5 times the normal physiological dose. In some embodiments, the upper normal limit is about 1.5 times the normal physiological dose. In some embodiments, the upper normal limit is about 2 times the normal physiological dose. In some embodiments, the upper normal limit is about 2.5 times the normal physiological dose. In some embodiments, the upper normal limit is about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3.0 times the normal physiological dose, or within a range defined by any of the foregoing values.

[0242] In some embodiments, the subject's glucocorticoid dosage is reduced by about 10% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 20% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 30% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 40% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 60% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 70% after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's glucocorticoid dosage is reduced by less than about 20% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 20% to about 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by more than about 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the subject's glucocorticoid dosage is reduced by about 10% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 20% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 30% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 40% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by about 60% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's glucocorticoid dosage is reduced by about 70% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's glucocorticoid dosage is reduced by less than about 20% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's glucocorticoid dosage is reduced by about 20% to about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's glucocorticoid dosage is reduced by more than about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in glucocorticoid dosage is relative to the glucocorticoid dosage prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the subject's glucocorticoid dose is reduced within a range defined by any of the above values.

[0245] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 25% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is less than 1.5 times the upper limit of normal after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of 17-hydroxyprogesterone are within normal limits after a period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least about 25% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is less than about 1.5 times the upper limit of normal after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of 17-hydroxyprogesterone are within normal limits after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the subject's 17-hydroxyprogesterone level is reduced to within a range defined by any of the above values.

[0248] In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 25% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 40% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the adrenocorticotropic hormone level is less than 1.5 times the upper limit of normal after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the adrenocorticotropic hormone level is within normal limits after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the level of adrenocorticotropic hormone is reduced by at least about 25% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least about 40% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the adrenocorticotropic hormone level is less than about 1.5 times the upper limit of normal after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the adrenocorticotropic hormone level is within normal limits after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the subject's adrenocorticotropic hormone level falls within a range defined by any of the above values.

[0251] In some embodiments, the androstenedione level is reduced by at least 25% after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the androstenedione level is relative to the androstenedione level before administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is reduced by at least 30% after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the androstenedione level is relative to the androstenedione level before administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is reduced by at least 50% after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the androstenedione level is relative to the androstenedione level before administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is less than 1.5 times the upper limit of normal after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is within normal limits after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the androstenedione level is reduced by at least about 25% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in androstenedione level is relative to the androstenedione level before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is reduced by at least about 30% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in androstenedione level is relative to the androstenedione level before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is reduced by at least about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in androstenedione level is relative to the androstenedione level before administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is less than about 1.5 times the upper limit of normal after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the androstenedione level is within normal limits after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the subject's androstenedione levels are reduced to within a range defined by any of the above values.

[0254] In some embodiments, the testosterone level decreases by at least 25% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the decrease in testosterone level is relative to the testosterone level prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the testosterone level decreases by at least 30% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the decrease in testosterone level is relative to the testosterone level prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the testosterone level decreases by at least 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the decrease in testosterone level is relative to the testosterone level prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the testosterone level is less than 1.5 times the upper limit of normal after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, testosterone levels are within normal limits after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the testosterone level is reduced by at least about 25% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in testosterone level is relative to the testosterone level prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the testosterone level is reduced by at least about 30% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in testosterone level is relative to the testosterone level prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the testosterone level is reduced by at least about 50% after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in testosterone level is relative to the testosterone level prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, testosterone levels are less than about 1.5 times the upper normal limit after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, testosterone levels are within normal limits after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the subject's testosterone level falls within a range defined by any of the above values.

[0257] In some embodiments, the 17-hydroxyprogesterone level is reduced by at least 50% and the androstenedione level is reduced by at least 50% after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the reduction in the 17-hydroxyprogesterone level and the androstenedione level are relative to the 17-hydroxyprogesterone level and the androstenedione level before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the 17-hydroxyprogesterone level is less than 1.5 times the upper limit of normal and the androstenedione level is less than 1.5 times the upper limit of normal. In some embodiments, after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the 17-hydroxyprogesterone level is within normal limits and the androstenedione level is within normal limits.

[0258] In some embodiments, after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the level of 17-hydroxyprogesterone is reduced by at least about 50%, and the level of androstenedione is reduced by at least about 50%, where the reductions in the levels of 17-hydroxyprogesterone and androstenedione are relative to the levels of 17-hydroxyprogesterone and androstenedione prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the level of 17-hydroxyprogesterone is less than about 1.5 times the upper limit of normal, and the level of androstenedione is less than about 1.5 times the upper limit of normal. In some embodiments, after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the level of 17-hydroxyprogesterone is within normal limits, and the level of androstenedione is within normal limits.

[0259] In some embodiments, the subject's 17-hydroxyprogesterone and androstenedione levels are reduced to within a range defined by any of the above values.

[0260] In some embodiments, the subject exhibits a reduced glucocorticoid load after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduced glucocorticoid load is relative to the glucocorticoid load prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, testicular adrenal quiescent tumor control, and fertility are improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, a subject exhibits a reduced glucocorticoid load after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduced glucocorticoid load is relative to the glucocorticoid load prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more symptoms of glucocorticoid load selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, testicular adrenal quiescent tumor control, and fertility are improved after a period of administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the quality of life as measured by EuroQol Five Item 5 level (EQ-5D-5L) in a subject is improved after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in EuroQol Five Item 5 level (EQ-5D-5L) is relative to the EuroQol Five Item 5 level (EQ-5D-5L) result prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, fatigue is reduced in a subject after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in fatigue is relative to fatigue prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, sleep is improved in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in sleep is relative to sleep prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, insulin resistance is reduced in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in insulin resistance is relative to the insulin resistance prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, glucose tolerance is decreased in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the decreased glucose tolerance is relative to glucose tolerance prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, glucose control in a subject is improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improved glucose control is relative to glucose control prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, in a subject, lipid levels reflective of dyslipidemia are reduced after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in lipid levels is relative to lipid levels prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, lipid levels reflective of hyperlipidemia are reduced in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in lipid levels is relative to lipid levels prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, bone mineral density is improved in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in bone mineral density is relative to bone mineral density prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, bone turnover is improved in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in bone turnover is relative to bone turnover prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, in a subject, fat mass is reduced after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in fat mass is relative to the fat mass prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, a subject's body weight is reduced after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in body weight is relative to the body weight prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, central obesity is reduced in a subject after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in central obesity is relative to central obesity prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, in a subject, blood pressure is improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in blood pressure is relative to blood pressure prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the severity of hirsutism is reduced in a subject after a period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in the severity of hirsutism is relative to the severity of hirsutism prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, in a subject, menstrual periodicity is improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improvement in menstrual periodicity is relative to the menstrual periodicity prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, in a subject, control of testicular adrenal rest tumors is improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improved control of testicular adrenal rest tumors is relative to control of testicular adrenal rest tumors prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, in a subject, fertility is improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improved fertility is relative to fertility prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, in a subject, gonadotropin levels are improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improved gonadotropin levels are relative to gonadotropin levels prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, in a subject, progesterone levels are increased after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the increased progesterone levels are relative to progesterone levels prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, in a subject, semen levels are improved after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the improved semen levels are relative to semen levels prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, in a subject, LH (luteinizing hormone) levels are increased after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the increased LH levels are relative to LH levels prior to administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the administration period is at least about 4 weeks. In some embodiments, the administration period is at least about 24 weeks. In some embodiments, the administration period is at least about 1 year. In some embodiments, the administration period is at least 4 weeks. In some embodiments, the administration period is at least 24 weeks. In some embodiments, the administration period is at least 1 year. In some embodiments, the administration period is less than about 1 day. In some embodiments, the administration period is about 1, 2, 3, 4, 5, 6, or 7 days, or within any of the values ​​recited above. In some embodiments, the administration period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks, or within any of the values ​​recited above. In some embodiments, the administration period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or within any of the values ​​recited above. It is understood that the comparative measurements are preferably carried out in the morning.

[0285] In some embodiments, the subject is a pediatric subject. In some embodiments, the pediatric subject is less than or equal to 6 years old. In some embodiments, the pediatric subject is greater than 6 years old and less than 11 years old. In some embodiments, the pediatric subject is greater than 10 years old and less than 15 years old. In some embodiments, the pediatric subject is greater than 14 years old and less than 19 years old.

[0286] In some embodiments, the subject is an adult subject. In some embodiments, the subject is over 18 years of age. In some embodiments, the subject is female. In some embodiments, the subject is male.

[0287] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition described herein. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition described in Example 9. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition described in Example 11. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition described in Example 12. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition described in Example 13. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a hydrochloride salt or a p-toluenesulfonate salt.

[0288] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a p-toluenesulfonate salt as described herein.

[0289] For the avoidance of doubt, there is also provided herein a corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the corresponding methods described herein.

[0290] For the avoidance of doubt, there is also provided herein the use of a corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the corresponding methods described herein.

[0291] For the avoidance of doubt, there is also provided herein the use of a corresponding pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the corresponding methods described herein.

[0292] p-Toluenesulfonate In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is the p-toluenesulfonic acid salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine.

[0293] In some embodiments, the p-toluenesulfonic acid salt of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is a crystalline salt. In some embodiments, the p-toluenesulfonic acid crystalline salt has Form 1.

[0294] In some embodiments, the crystalline salt of p-toluenesulfonic acid has an X-ray powder diffraction pattern substantially as shown in Figure 27. In some embodiments, the crystalline salt of p-toluenesulfonic acid has a DSC thermogram substantially as shown in Figure 28. In some embodiments, the crystalline salt of p-toluenesulfonic acid has a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 28.

[0295] In some embodiments, the crystalline salt of p-toluenesulfonic acid has at least one X-ray powder diffraction (XRPD) peak selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees in terms of two-theta (±0.2 degrees). In some embodiments, the crystalline salt of p-toluenesulfonic acid has at least two X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees in terms of two-theta (±0.2 degrees). In some embodiments, the crystalline salt of p-toluenesulfonic acid has at least three X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees in terms of two-theta (±0.2 degrees). In some embodiments, the crystalline salt of p-toluenesulfonic acid has at least four X-ray powder diffraction (XRPD) peaks selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees in terms of two-theta (±0.2 degrees). In some embodiments, the crystalline salt of p-toluenesulfonic acid has characteristic X-ray powder diffraction (XRPD) peaks at 9.1, 11.3, 13.2, 16.3, and 21.1 degrees in terms of two-theta (±0.2 degrees). In some embodiments, the crystalline salt of p-toluenesulfonic acid has an endothermic peak with an onset of melting at about 156° C. (22.2 J / g) in a differential scanning calorimetry (DSC) thermogram.

[0296] Lipid-based semi-solid preparations (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and (b) one or more of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer Provided herein is a lipid-based semi-solid formulation, which is a pharmaceutical composition comprising:

[0297] In some embodiments, the pharmaceutical composition comprises about 1% to about 20% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 5% to about 15% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 10% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or within any of the ranges recited above.

[0298] In some embodiments, the pharmaceutical composition comprises an oil phase vehicle. The oil phase vehicle is a solvent that is poorly miscible with water. In some embodiments, the pharmaceutical composition comprises about 1% to about 50% by weight of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 20% to about 50% by weight of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35% to about 45% by weight of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 39% by weight of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45% by weight of the oil phase vehicle, or within any of the ranges recited above.

[0299] In some embodiments, the oil phase vehicle is selected from medium-chain triglycerides, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the oil phase vehicle is a medium-chain triglyceride. In some embodiments, the medium-chain triglyceride is Labrafac™ Lipophile WL1349. In some embodiments, the medium-chain triglyceride is Miglyol 812N.

[0300] In some embodiments, the pharmaceutical composition comprises an emulsifier. An emulsifier is a compound or substance that acts as a stabilizer for emulsions. In some embodiments, the pharmaceutical composition comprises about 5% to about 50% by weight of emulsifier. In some embodiments, the pharmaceutical composition comprises about 10% to about 30% by weight of emulsifier. In some embodiments, the pharmaceutical composition comprises about 15% to about 25% by weight of emulsifier. In some embodiments, the pharmaceutical composition comprises about 20% by weight of emulsifier. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% by weight of emulsifier, or within any of the ranges recited above.

[0301] In some embodiments, the emulsifier is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the emulsifier is propylene glycol dicaprylate / dicaproate. In some embodiments, the propylene glycol dicaprylate / dicaproate is Labrafac™ PG.

[0302] In some embodiments, the pharmaceutical composition comprises a nonionic surfactant. A nonionic surfactant is a substance with an uncharged hydrophilic head and a hydrophobic tail that is a formulation component added to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition comprises about 5% to about 50% by weight of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 10% to about 30% by weight of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 15% to about 25% by weight of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 19% by weight of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% by weight of a nonionic surfactant, or within any of the ranges recited above.

[0303] In some embodiments, the nonionic surfactant is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, Gelucire, lauroyl polyoxyl-32 glyceride, poloxamer, PEG-32 stearate, and PEG-32 hydrogenated palm oil glyceride. In some embodiments, the nonionic surfactant is lauroyl polyoxyl-32 glyceride. In some embodiments, the lauroyl polyoxyl-32 glyceride is Gelucire® 44 / 14.

[0304] In some embodiments, the pharmaceutical composition comprises a solubilizing agent. A solubilizing agent is a solvent that aids in dissolving the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1% to about 50% by weight of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 1% to about 20% by weight of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 5% to about 15% by weight of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 11% by weight of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% by weight of the solubilizing agent, or within any of the ranges recited above.

[0305] In some embodiments, the solubilizing agent is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glyceride, and poloxamer. In some embodiments, the solubilizing agent is vitamin E polyethylene glycol succinate. In some embodiments, the vitamin E polyethylene glycol succinate is Kolliphor® TPGS. In some embodiments, the vitamin E polyethylene glycol succinate is vitamin E / TPGS 260.

[0306] In some embodiments, the pharmaceutical composition comprises: (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof (b) Oil phase vehicle (c) Emulsifiers (d) nonionic surfactants, and (e) Solubilizer Includes.

[0307] In some embodiments, the pharmaceutical composition comprises: (a) about 5% to about 15% by weight, based on the weight of the free base, of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof (b) about 35% to about 45% by weight of an oil phase vehicle (c) about 15% to about 25% by weight of an emulsifier (d) about 15% to about 25% by weight of a nonionic surfactant, and (e) about 5% to about 15% by weight of a solubilizing agent Includes.

[0308] In some embodiments, the pharmaceutical composition comprises: (a) about 10% by weight, based on the weight of the free base, of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof; (b) about 39% by weight of an oil phase vehicle (c) about 20% by weight of an emulsifier (d) about 19% by weight of a nonionic surfactant, and (e) about 11% by weight of a solubilizing agent Includes.

[0309] In some embodiments, the pharmaceutical composition comprises: (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) Medium-chain triglyceride components (c) Propylene Glycol Dicaprylate / Dicaproate Component (d) a lauroyl polyoxyl-32 glyceride component, and (e) Vitamin E polyethylene glycol succinate component Includes.

[0310] In some embodiments, the pharmaceutical composition comprises: (a) about 5% by weight to about 15% by weight of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) about 35% to about 45% by weight of medium-chain triglycerides (c) about 15% to about 25% by weight of propylene glycol dicaprylate / dicaproate (d) about 15% to about 25% by weight of lauroyl polyoxyl-32 glyceride, and (e) about 5% to about 15% by weight of vitamin E polyethylene glycol succinate Includes.

[0311] In some embodiments, the pharmaceutical composition comprises: (a) approximately 10% by weight of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (b) approximately 39% by weight of medium-chain triglycerides (c) about 20% by weight of propylene glycol dicaprylate / dicaproate (d) about 19% by weight of lauroyl polyoxyl-32 glyceride, and (e) about 11% by weight of vitamin E polyethylene glycol succinate Includes.

[0312] In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity of about 15 to about 40 centipoise at about 45° C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity of about 26 to about 30 centipoise at about 45° C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity of about 5 to about 25 centipoise at about 60° C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity of about 14 to about 18 centipoise at about 60° C.

[0313] In some embodiments, the pharmaceutical composition does not include the combination of mannitol, croscarmellose sodium, corn starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0314] In some embodiments, the pharmaceutical composition does not include at least one of mannitol, croscarmellose sodium, corn starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0315] In some embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an amorphous form of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises the compound of formula (I) as a free base. In some embodiments, the crystalline form of the compound of formula (I) is Form I.

[0316] In some embodiments, the pharmaceutical composition is formulated in a unit dosage form, and the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 200 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 75 mg to about 150 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 50 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 100 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 25 mg, based on the weight of the free base.

[0317] In some embodiments, the pharmaceutical composition is in the form of a tablet, capsule, sachet, powder, granule, coated particle, coated tablet, enteric coated tablet, enteric coated capsule, melt strip, or melt film. In some embodiments, the pharmaceutical composition is in tablet form. In some embodiments, the pharmaceutical composition is in capsule form. In some embodiments, the dosage form is coated.

[0318] Some embodiments provide a method for preparing a pharmaceutical composition, comprising: (a) heating a mixture of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer; (b) mixing the mixture of step (a) until a uniform mixture is obtained; and (c) mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with the homogenous mixture of step (b) until the compound of formula (I) or a pharmaceutically acceptable salt thereof dissolves to form a composition. The present invention provides a method comprising:

[0319] In some embodiments, the method comprises: (d) encapsulating the composition of step (c) in a capsule shell to form a capsule; and (e) banding the capsules of step (d) in a mixture of a banding agent and a banding solvent. Further includes:

[0320] Liquid formulations (a) a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (b) one or more of a sweetener, an antioxidant, and a flavoring agent; and (c) Liquid vehicle Provided herein is a pharmaceutical composition in oral solution dosage form comprising:

[0321] In some embodiments, the pharmaceutical composition comprises about 1% w / v to about 50% w / v of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 1% w / v to about 10% w / v of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 5% w / v of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / v of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or within any of the ranges recited above.

[0322] In some embodiments, the pharmaceutical composition comprises a sweetener. A sweetener is a formulation component added to improve taste. In some embodiments, the pharmaceutical composition comprises about 0.01% w / v to about 1.5% w / v of a sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1% w / v to about 0.5% w / v of a sweetener. In some embodiments, the pharmaceutical composition comprises about 0.15% w / v of a sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5% w / v of a sweetener, or within any of the ranges recited above.

[0323] In some embodiments, the sweetening agent is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame, hi some embodiments, the sweetening agent is...

Claims

[Claim 1] The invention as depicted in the drawings.

Images