CRF1 RECEPTOR ANTAGONIST, PHARMACEUTICAL FORMULATIONS AND ITS SOLID FORMS FOR THE TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA

Abstract

Provided are 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. 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 the treatment of congenital adrenal hyperplasia (CAH).

Description

TECHNICAL FIELD

[0001] The present disclosure relates to 4-(2-chloro-4-methoxy5-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 treatment of 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 use in the treatment of congenital adrenal hyperplasia (CAH).BACKGROUND

[0002] Classic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders that result in an enzyme deficiency that alters the production of adrenal steroids due to 21-hydroxylase deficiency, a condition that results 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 cause adrenal hyperplasia and the enzyme mutation causes a shunting of cortisol precursor steroids to alternate pathways. Most notably, the shunting of androgens leads to virilization and other developmental complications in females and the over-accumulation of ACTH is associated with the formation of testicular adrenal rest tumors in males. In addition, since the same enzyme (21-hydroxylase) is used in the pathway for the biosynthesis of the mineralocorticoids, a number of these patients suffer from aldosterone deficiency which can result in dehydration and death due to salt-wasting. The prevalence of classic 21-hydroxylase deficiency CAH in the US general population, based on newborn screening, has been documented as 1:10,000 to 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 females in particular, appear to be the most vulnerable population of CAH sufferers and represent the subgroup of patients with the greatest unmet medical need (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 younger patients results in early onset puberty and adrenarche, changes in skeletal maturation patterns, short stature caused by premature growth plate fusion, as well as significant hirsutism and acne problems. While survival is properly ensured through steroid replacement strategies based on physiologic dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these doses are often inadequate to suppress the accumulating ACTH and overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). The uncontrolled symptoms of androgen excess, indeed, have a substantial impact on the day-to-day functioning and development of these patients.

[0004] Currently, exogenous corticosteroids are the standard of care for treating patients with classic CAH. This treatment is used to correct the cortisol deficiency and reduce the excessive ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH are typically well above the normal physiological level used for cortisol replacement alone (as in patients with Addison's disease). This increased exposure to glucocorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth velocity, 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).

[0005] Corticotropin releasing factor (CRF) is a hypothalamic hormone released directly into the hypophyseal portal vasculature and acts on specific corticotropin releasing factor 1 (CRF1) receptors on corticotropes in the anterior pituitary to stimulate the release of ACTH. Blockade of these receptors has been shown to decrease the release of ACTH in both animals and humans. Therefore, compounds that block CRF1 receptors have the potential to directly inhibit the excessive ACTH release that occurs in CAH and thereby allow for normalization of androgen production while using lower, more physiologic doses of hydrocortisone.

[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, 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 hereby incorporated by reference in its entirety. The compound of Formula (I) is a low solubility compound with low bioavailability. Partially due to its low solubility, attempts at formulating the compound of Formula (I) have proven to be difficult, particularly for formulations suitable for pediatric administration.

[0007] Thus, there is a need for a treatment for CAH that avoids the severe complications associated with corticosteroid therapy. There is also a need for a formulation of the compound of Formula (I) with increased bioavailability and a need for a formulation of the compound of Formula (I) that is suitable for pediatric administration. The formulations and methods of the present invention help address these and other needs.SUMMARY

[0008] Provided herein is a pharmaceutical composition comprising: (a) a compound of Formula (I): or a pharmaceutically acceptable salt thereof; and (b) one or more of an oily phase vehicle, an emulsifying agent, a nonionic surfactant, and a solubilizing agent.

[0009] Provided herein is a pharmaceutical composition in oral solution dosage form comprising: (a) a compound of Formula (I): or a pharmaceutically acceptable salt thereof; (b) one or more of a sweetener, an anti-oxidant, and a flavor; and (c) a liquid vehicle.

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

[0011] Provided herein is a method for treating congenital adrenal hyperplasia (CAH) 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 having the Formula (I): 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 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 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 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 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, the reduction in level of any of biomarkers is determined by comparing the level of the biomarker as measured during the circadian release on a day prior to 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 and the level of the biomarker as measured during the circadian release on the day after 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. In some embodiments, the circadian release occurs between the hours of 2 a.m. and 10 a.m.

[0018] In some embodiments, 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 three to eight 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, 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%.

[0021] In some embodiments, the level of androstenedione is reduced by at least 25%. In some embodiments, the level of androstenedione is reduced by at least 30%. In some embodiments, the level of androstenedione is 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, 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 at 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, 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.

[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 impairment in a subject having 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, in an amount sufficient to reduce the level of androstenedione in the subject. In some embodiments, the growth impairment is selected from one or more of accelerated height velocity, accelerated weight velocity, 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 of reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in a subject having classic congenital adrenal hyperplasia, wherein the compound, or pharmaceutically acceptable salt thereof, is administered in an amount sufficient to reduce the level of androstenedione in the subject.

[0027] Also provided herein is 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 severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in a subject having classic congenital adrenal hyperplasia, wherein the compound, or pharmaceutically acceptable salt thereof, is administered in an amount sufficient to reduce the level of androstenedione in the subject.

[0028] In some embodiments, the level of androstenedione is reduced by at least 25%. In some embodiments, the level of androstenedione is reduced by at least 30%. In some embodiments, the level of androstenedione is reduced by at least 50%.

[0029] Provided herein is a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject having 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.

[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 having congenital adrenal hyperplasia.

[0031] Also provided herein is 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 having 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 of reducing the dosage of corticosteroid administered to a subject having congenital adrenal hyperplasia for controlling 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 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 corticosteroid administered to a subject having congenital adrenal hyperplasia.

[0035] Also provided herein is 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 dosage of corticosteroid administered to a subject having congenital adrenal hyperplasia.

[0036] Provided herein is a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject having 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, wherein the side effect is selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing 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, dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infections, and reactivation of latent infections.

[0037] 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 severity of one or more side effects of glucocorticoid treatment in a subject having congenital adrenal hyperplasia, wherein the side effect is selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing 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, dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infections, and reactivation of latent infections.

[0038] Also provided herein is 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 severity of one or more side effects of glucocorticoid treatment in a subject having congenital adrenal hyperplasia, wherein the side effect is selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing 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, dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infections, and reactivation of latent infections.

[0039] In some embodiments, 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 at an amount sufficient to reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% as compared to the level prior to administration.

[0040] In some embodiments, 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 at an amount sufficient to reduce the level of androstenedione by at least 30% as compared to the level prior to administration.

[0041] In some embodiments, 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 at an amount sufficient to (a) reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% as compared to the level prior to administration; and (b) reduce the level of androstenedione by at least 30% as compared to the level prior to administration.

[0042] In some embodiments, 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 at an amount equivalent to from about 25 mg to about 150 mg 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, 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 at 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, 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.

[0045] Provided herein is 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 if the level of the one or more biomarkers is elevated compared to a healthy subject not having congenital adrenal hyperplasia; and (iii) 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 if the subject is determined to have elevated levels of the one or more biomarkers.

[0046] 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 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 if the level of the one or more biomarkers is elevated compared to a healthy subject not having congenital adrenal hyperplasia; and (iii) administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(lS)-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 is determined to have elevated levels of the one or more biomarkers.

[0047] Also provided herein is 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 method comprises: (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 if the level of the one or more biomarkers is elevated compared to a healthy subject not having congenital adrenal hyperplasia; and (iii) administering to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(lS)-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 is determined to have elevated levels of the one or more biomarkers.

[0048] In some embodiments, the method further comprises (iv) measuring the level of the one or more biomarkers 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, in a biological sample obtained from the subject to determine whether the subject has reduced levels of the one or more biomarkers as compared with the measurement of step (i). In some embodiments, the method further comprises (v) 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 reduced levels of the one or more biomarkers.

[0049] In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject in a similar manner and within a same time of day window. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject within the time of day window from 2 a.m. to 10 a.m. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject within the time of day window from 6 a.m. to 10 a.m.

[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 the levels of (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione.

[0052] In some embodiments, step (i) comprises measuring the level of 17-hydroxyprogesterone (17-OHP), wherein the level of 17-hydroxyprogesterone (17-OHP) is elevated when 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 when it is greater than 200 ng / dL.

[0054] In some embodiments, the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cycloptopyl-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 at an amount equivalent to from 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, 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 at 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, 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.

[0055] 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 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, where in 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 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, 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 with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement comprising about 1500 calories per liter with a caloric 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 administration of 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.

[0059] In some embodiments, 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 with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement comprising 1500 calories per liter with a caloric 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 administration of 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.

[0060] In some embodiments, 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, exhibits a positive food effect. In some embodiments, the positive food effect is measured in terms of C max , AUC, or combinations thereof when comparing oral administration of 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, in the fed and fasting states.

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

[0062] Provided herein is a method of reducing glucocorticoid burden in a subject as measured after a time period of administration 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, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound, or 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 burden in a subject, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound, or pharmaceutically acceptable salt thereof.

[0064] Also provided herein is 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 burden in a subject, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound, or pharmaceutically acceptable salt thereof.

[0065] Provided herein is a method of 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility in a subject having 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 symptom is improved after a time period of administration of the compound, or pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the compound, or pharmaceutically acceptable salt thereof.

[0066] 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 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility in a subject having classic congenital adrenal hyperplasia, wherein the symptom is improved after a time period of administration of the compound, or pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the compound, or pharmaceutically acceptable salt thereof.

[0067] Also provided herein is 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 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility in a subject having classic congenital adrenal hyperplasia, wherein the symptom is improved after a time period of administration of the compound, or pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the compound, or 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] Also provided herein is use of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(lS)-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 manufacture of a medicament for use in any of the methods disclosed herein.

[0070] Also provided herein is a spray-dried dispersion containing 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 (I): 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 from about 1:9 to about 1:1.

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

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

[0073] In some embodiments, the polymer is a pyrrolidone polymer. In some embodiments, the pyrrolidone polymer is selected from polyvinyl pyrrolidone (PVP) and a polyvinyl pyrrolidone 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 at a ratio of about 40:60 to about 60:40 by weight. In some embodiments, the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 60:40 by weight. In some embodiments, the copolymer has the structure: wherein the value of n is about 1 to about 2 times the value of m. In some embodiments, the copolymer is copovidone, wherein 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] 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 (I): or a pharmaceutically acceptable salt thereof; and a polymer that is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the structure: 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 at a ratio of about 60:40 by weight; and wherein the weight ratio of the compound of Formula (I) to the copolymer is from 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 homogeneous particles. In some embodiments, the particles have a particle size distribution D 50 of about 5 µm to about 100 µm. In some embodiments, the particles have a particle size distribution D 50 of about 10 µm to about 50 µm. In some embodiments, the particles have a particle size distribution D 50 of about 15 µm to about 30 µm.

[0076] In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is from about 1:1.5 to about 1:9. In some embodiments, the weight ratio of the compound of Formula (I) to the polymer is from 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 less than about 2 wt %. In some embodiments, the particles have a residual solvent content less than about 1 wt %. In some embodiments, the particles have a residual solvent content of about 0.5 wt % or less.

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

[0079] Also provided herein is a method for preparing a spray-dried dispersion of the present disclosure, comprising: 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 produce the spray-dried dispersion, wherein the spray-drying forms homogeneous particles of the compound of Formula (I) and the polymer.

[0080] In some embodiments, the method comprises removing the organic solvent after formation of the spray-dried dispersion by drying the spray-dried dispersion. In some embodiments, the spray-dried dispersion is dried with 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 about 25°C to about 45°C. In some embodiments, the spray dryer outlet temperature is about 35°C.

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

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

[0085] Also provided herein is a pharmaceutical composition 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 excipients are 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 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. 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, granules, coated particle, coated tablet, enterocoated tablet, enterocoated capsule, melting strip, or melting 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 the AUC in the fed state to the AUC in the fasted state of about 5 to about 10. In some embodiments, wherein the spray-dried dispersion has a ratio of the C max in the fed state to the C max in the fasted state of about 5 to about 10.

[0090] Also provided herein is a method for preparing a pharmaceutical composition, comprising combining the 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 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 the pharmaceutical composition is administered to the subject in a fed state. In some embodiments, the spray-dried dispersion or the pharmaceutical composition is administered to the subject with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement comprising about 1000 to about 2000 calories per liter with a fat content greater than 30%. In some embodiments, the nutritional composition is a liquid dietary supplement comprising 1500 calories per liter with a caloric 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 administration of the spray-dried dispersion or the pharmaceutical composition.

[0095] In some embodiments, administering the spray-dried dispersion or the pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is measured in terms of C max , AUC, or combinations thereof when comparing oral administration of the spray-dried dispersion or pharmaceutical composition in the fed and fasting states. In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasted state is about 5 to about 10. In some embodiments, the ratio of the C max in the fed state to the C max in the fasted state is about 5 to about 10. In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasted state is about 10 to about 20. In some embodiments, the ratio of the Cmax in the fed state to the C max in the fasted state 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, for example, for use in any of the methods disclosed herein.

[0098] Also provided herein is use of a spray-dried dispersion of the present disclosure for 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 administering to the subject a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0100] Also provided herein is a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of the 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 use of pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of the 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 is pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, for example, for use in any of the methods disclosed herein.

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

[0104] Also provided herein is a method of 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 the compound of Formula (I) which has not been 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 of improving gastrointestinal absorption of a compound of Formula (I) in a subject, wherein the improvement is relative to oral administration of the compound of Formula (I) which has not been prepared as a spray-dried dispersion.

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

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

[0108] Also provided herein is a method of improving 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 the compound of Formula (I) which has not been 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 oral bioavailability of a compound of Formula (I) in a subject, wherein the improvement is relative to oral administration of the compound of Formula (I) which has not been prepared as a spray-dried dispersion.

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

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

[0112] Also provided herein is a crystalline salt, 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, p-toluenesulfonic acid salt.

[0113] Also provided herein is a crystalline salt, 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, p-toluenesulfonic acid salt, for use in therapy, for example, for use in any of the methods disclosed herein.

[0114] Also provided herein is use of a crystalline salt, 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, p-toluenesulfonic acid salt, for 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 be apparent from the following detailed description and figures, and from the claims.DESCRIPTION OF DRAWINGS

[0116] FIG. 1 shows 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. FIG. 2 shows the vertical membrane flux cell integrated in the µDiss Profiler ™< used for the membrane flux assay. FIG. 3 shows non-sink dissolution data for several spray-dried dispersion formulations and the compound of Formula (I) in 0.5 wt% SIF in PBS, pH 6.5. FIG. 4 is a graph showing membrane flux of 1 mg / mL GB / IB 0.5 wt% SIF doses of the compound of Formula (I) and various spray-dried dispersion formulations over time. The solid lines indicate flux (µg min -1< cm -2< ) and the broken lines indicate concentration (µg / mL) in 0.5% SIF. FIG. 5 is a flow diagram of the spray drying manufacturing process used to prepare a 1000 g batch of a SDD containing 25% of the compound of Formula (I) and 75% PVP / VA 64. FIGS. 6A and 6B are line graphs showing the pharmacokinetic results of a bioavailability and food effect study in dogs. FIG. 6A shows the results from Cohort 1 and FIG. 6B shows the results from Cohort 2. FIG. 7 is a flow chart showing the study design of a Phase 1 study of the pharmacokinetics and food effect of the compound of Formula (I) in healthy adult subjects. FIGS. 8A and 8B are line graphs showing the mean plasma concentration versus time profiles for the compound of Formula (I) under fasted and fed conditions, respectively, in healthy adult subjects. FIGS. 9A-9C are spaghetti plots of the pharmacokinetics of the compound of Formula (I) in healthy adult subjects under fasted and fed conditions. FIG. 9A shows the AUC 0-tlast values. FIG. 9B shows the AUC 0-∞ values. FIG. 9C shows the C max values. FIG. 10 is a flow chart showing the study design of a Phase 1 study of the bioavailability, pharmacokinetics and food effect of the compound of Formula (I) in healthy adult subjects. FIG. 11 shows the study design of a Phase 2 study of the compound of Formula (I) in adult subjects with congenital adrenal hyperplasia. FIGs. 12A and 12B show the arithmetic mean values for adrenocorticotropic hormone (ACTH) (FIG. 12A) and 17-hydroxyprogesterone (17-OHP) (FIG. 12B) for all 8 Cohort 1 subjects plotted at each time point for pre-treatment baseline (circles), day 1 (squares), and day 14 (triangles). FIGs. 13A and 13B show arithmetic mean values for androstenedione (FIG. 13A) and testosterone (FIG. 13B) for all 8 Cohort 1 subjects were plotted at each timepoint for pre-treatment baseline (circles), day 1 (squares), and day 14 (triangles). FIGs. 14A and 14B show the reduction of ACTH at timepoints 8-, 10-, and 12-hours postdose. FIG 14A shows the values for each time point as compared to baseline. FIG. 14B shows the mean values across all three timepoints. FIGs. 15A and 15B show the reduction of 17-OHP at timepoints 8-, 10-, and 12-hours postdose. FIG 15A shows the values for each time point as compared to baseline. FIG. 15B shows the mean values across all three timepoints. FIGs. 16A and 16B show the reduction of androstenedione at timepoints 8-, 10-, and 12-hours postdose. FIG 16A shows the values for each time point as compared to baseline. FIG. 16B shows the mean values across all three timepoints. FIG. 17A shows the plasma ACTH Mean Blood Concentrations following the compound of Formula (I) 50 mg Dose qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning window timepoint. ACTH normal ranges: Female 6 to 58 pg / mL; Male 7 to 69 pg / mL. FIG. 17B shows the serum 17-OHP Mean Blood Concentrations following the compound of Formula (I) 50 mg Dose qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning window timepoint. 17-OHP normal ranges: Female < 207 ng / dL; Male < 139 ng / dL. FIG. 17C: shows the serum Androstenedione Mean Blood Concentrations following the compound of Formula (I) 50 mg Dose qhs (Cohort 1; n=8). Error bars represent the standard error of the mean for each morning window timepoint. Androstenedione normal ranges: Female 26 to 214 ng / mL; Male 33 to 134 ng / mL. FIG. 18A shows the plasma ACTH Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning window timepoint. ACTH normal ranges: Female 6 to 58 pg / mL; Male 7 to 69 pg / mL. FIG. 18B shows the serum 17-OHP Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning window timepoint. 17-OHP normal ranges: Female < 207 ng / dL; Male < 139 ng / dL. FIG. 18C shows the serum Androstenedione Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose qhs (Cohort 2; n=4). Error bars represent the standard error of the mean for each morning window timepoint. Androstenedione normal ranges: Female 26 to 214 ng / mL; Male 33 to 134 ng / mL. FIG. 19A shows the plasma ACTH Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose with Evening Meal (Cohort 3). Error bars represent the standard error of the mean for each morning window timepoint. ACTH normal ranges: Female 6 to 58 pg / mL; Male 7 to 69 pg / mL. FIG. 19B shows the serum 17-OHP Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose with Evening Meal (Cohort 3). Error bars represent the standard error of the mean for each morning window timepoint. 17-OHP normal ranges: Female < 207 ng / dL; Male < 139 ng / dL. FIG. 19C shows the serum Androstenedione Mean Blood Concentrations following the compound of Formula (I) 100 mg Dose with Evening Meal (Cohort 3). Error bars represent the standard error of the mean for each morning window timepoint. Androstenedione normal ranges: Female 26 to 214 ng / mL; Male 33 to 134 ng / mL. FIG. 20 is a scheme showing the manufacturing process for forming 50 mg capsules of the compound of Formula (I). FIG. 21 is an alternative scheme showing the manufacturing process for forming 50 mg capsules of the compound of Formula (I). FIGs. 22A and 22B show a scheme showing the manufacturing process for forming SDD granules of the compound of Formula (I). FIG. 23 is a scheme showing the manufacturing process for forming 50 mg / nL liquid formulation 1 of the compound of Formula (I). FIG. 24 is a scheme showing the manufacturing process for forming 50 mg / nL liquid formulation 2 of the compound of Formula (I). FIG. 25 is an XRPD spectrum of the compound of Formula (I) free base crystalline form I. FIG. 26 is a DSC spectrum of the compound of Formula (I) free base crystalline form I. FIG. 27 is an XRPD spectrum of the compound of Formula (1) tosylate crystalline form 1. FIG. 28 is a DSC and TGA spectrum of the compound of Formula (I) tosylate crystalline form 1. DETAILED DESCRIPTION

[0117] As described herein, 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 (I): or a pharmaceutically acceptable salt thereof, is a selective CRF1 receptor antagonist that has been found to be effective treating congenital adrenal hyperplasia. Specifically, the compound of Formula (I) has been found to effectively reduce several biomarkers associated with congenital adrenal hyperplasia.

[0118] Newborn screening for CAH is performed by immunoassay to measure 17-OHP levels in heel-stick capillary blood specimens obtained within the first 72 hours of life. The blood sample is analyzed for 17-OHP by commercially available dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA; PerkinElmer, Waltham Massachusetts) (White et al., J. Pediatr. 163:10-12 (2013)). Second-tier screening tests utilizing biochemical and molecular genetic testing methods, performed between 8 and 14 days of life, are employed by nine states in the United States and strongly recommended by an additional 5 states. The biochemical method includes immunoassay with 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). The genetic screen looks for CYP21A2 mutations that are associated with CAH. While not widely employed in the U.S., the addition of a second screening could potentially improve the sensitivity of the overall screening process, where sensitivity of the first screen alone is approximately 72%.

[0119] In absence of results from the newborn screening, female infants with classical CAH are typically identified due to the presence of ambiguous genitalia. Males have normal genitalia at birth and therefore are not diagnosed unless newborn screening is conducted or other medical complications come to attention. Infants who are not initially diagnosed with CAH and suffer from the salt-wasting form of the disease are later diagnosed in the setting of poor weight gain, vomiting, hyperkalemia and hyponatremia within the first few weeks of life.

[0120] Treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. Glucocorticoids are the current standard treatment in CAH and are used both to correct the endogenous cortisol deficiency and for reducing the elevated ACTH levels from the pituitary, which drives increased androgen production. Unlike the treatment of Addison's disease (adrenal insufficiency), in which cortisol replacement is sufficient, the treatment of CAH must also reduce ACTH production, to control the subsequent androgen excess as well. Thus, the goals of glucocorticoid treatment include cortisol replacement and suppression of ACTH to prevent virilization and menstrual disturbances in women and to inhibit testicular adrenal rest tumors in men. Mineralocorticoid replacement is needed to achieve normal plasma renin activity for maintenance of regular blood pressure, electrolyte balance, and volume status in those patients with the salt-wasting form of CAH.

[0121] The regimen of glucocorticoid treatment must support normal physiology and also ensure that sufficient cortisol is available during events that may elicit 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 in an effort to adequately suppress androgen production, or Addisonian syndrome due to under-treatment.

[0122] Overtreatment with mineralocorticoids may cause hypertension while under-treatment may lead to low blood pressure, salt loss, fatigue and increased requirements for glucocorticoids. Typical laboratory tests for monitoring treatment efficacy include measurement of plasma concentrations of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes. Adult patients with CAH have an increased prevalence of risk factors for cardiovascular disease including obesity, hypertension, and insulin resistance (see, e.g., Kim et al., Semin. Reprod. Med. 27(4):316-21 (2009)). A study of a large cohort of pediatric and adult CAH patients (n=244) demonstrated that patients are prescribed a variety of glucocorticoid treatment regimens yet frequently suffer from poor hormonal control and the aforementioned adverse outcomes (see, e.g., Finkielstain et al., J. Clin. Endocrinol Metab. 97(12):4429-38 (2012)).

[0123] Treatment of CAH includes efforts to normalize the cortisol deficiency with glucocorticoids (usually hydrocortisone in children but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults) and, if necessary for salt-wasting, mineralocorticoids (usually fludrocortisone). The glucocorticoid doses required to achieve sufficient suppression of excess androgens, however, are usually well above the normal physiologic dose used for cortisol replacement alone as in patients with Addison's disease. This increased exposure to glucocorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, and decreased bone mineral density in CAH patients (see, 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, P.W., et al. J. Clin. Endocrinol Metab. November 2018, 103(11): 1-46). This article is incorporated by reference in its entirety.

[0124] Corticotropin-releasing factor (CRF) was isolated from ovine hypothalami and identified as a 41-amino acid peptide. CRF has been found to produce profound alterations in endocrine, nervous, and immune system function. CRF is believed to be the major 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 (see, e.g., Vale et al., Science 213:1394-1397,1981). Secretion of CRF causes release of ACTH from corticotrophs in the anterior pituitary via binding to the CRF 1 receptor, a member of the class B family of G-protein coupled receptors.

[0125] Due to the physiological significance of CRF, the development of biologically-active small molecules having significant CRF 1 receptor binding activity and which are capable of antagonizing the CRF 1 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.

[0126] The pituitary hormone ACTH, under the control of hypothalamic corticotropin-releasing factor (CRF), stimulates uptake of cholesterol and drives the synthesis of pregnenolone initiating steroidogenesis in the adrenal gland. The adrenal cortex is comprised of three zones, which produce distinct classes of hormones many of which are driven by ACTH mobilizing cholesterol through this pathway. Deficiencies in these enzymes as a result of mutation or deletion cause the substrate concentrations to increase. In the most common form of CAH resulting from mutations or deletions in the 21-hydroxylase gene (CYP21A2), potent androgens are produced by the adrenal because of the accumulation of the steroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP). Plasma levels of 17-OHP can reach 10-1000 times the normal concentration in these cases. These increases result in the overproduction of androgens, specifically androstenedione, testosterone, and dihydroxytestosterone causing virilization in females. In addition, 21-hydroxylase deficiency in CAH causes 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. The lack of glucocorticoid synthesis and release eliminates the restraint on the hypothalamus and pituitary, which causes ACTH levels to increase. The excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting in adrenal hyperplasia.Definitions

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and 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, will control.

[0128] The term "about" preceding a value for DSC, TGA, or T g , which are reported as degrees Celsius, have an allowable variability 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 includes more specifically values of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0129] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that when a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any range therein.

[0130] "Room temperature" or "RT" refers to the ambient temperature of a typical laboratory, which is typically around 25°C.

[0131] "Spray-drying" refers to the method of producing a dry powder from a solution or slurry. The solution or slurry is atomized or rapidly dried with a hot gas, e.g., air or nitrogen, that causes the solvent to evaporate quickly and uniformly. A "spray-dried dispersion" refers to the powder obtained from the spray-drying process.

[0132] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the fonnulations. In addition, various excipients, such as are commonly used in the art, can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0133] "Subject," as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the subject is a human.

[0134] In some embodiments, the subject has experienced and / or exhibited 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 as having congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has a clinical record indicating that the subject has CAH (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.

[0135] The term "pediatric subject" as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. 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, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0136] As used herein, the terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0137] The term "preventing," as used herein, means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0138] The term "administration" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0139] As used herein, "therapeutically effective amount" is an amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising the compound of Formula (I), which is sufficient to achieve the desired effect and can vary according to the nature and severity of the disease condition, and the potency of the compound. A therapeutic effect is the relief, to some extent, of one or more of the symptoms of the disease, and can include curing a disease. "Curing" means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease can exist even after a cure is obtained (such as, e.g., extensive tissue damage).

[0140] The term "amorphous" means a solid in a solid state that is a non-crystalline state. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. The solid state form of a solid may be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those of skill in the art.

[0141] As used herein, "time of day window" refers to a period of time defined by a window start time and a window stop time. These times all refer to local times where a sample was taken. The phrase "same time of day window" when referring to samples taken from the subject mean, e.g., that a sample taken at 8:15 a.m. and a sample taken at 9:15 a.m. are considered to be taken in the same time of day window of, e.g., 2 a.m. to 10 a.m. or 6 a.m. to 10 a.m.Methods

[0142] The present disclosure relates to methods of treating congenital adrenal hyperplasia (CAH). The methods include administering to a subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering to a subject a therapeutically effective amount of a SDD of the present disclosure that includes a polymer and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering to a subject a therapeutically effective amount of pharmaceutical composition of the present disclosure that contains a SDD that includes a polymer and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0143] Provided herein is a method of 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 levels of elevated biomarkers or increasing levels of depressed biomarkers as compared to subject without CAH.

[0144] Provided herein is a method of 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.

[0145] In some embodiments, the reduction in level of any of the biomarkers (e.g., any of 17-OHP, ACTH, and androstenedione) is determined by comparing the level of the biomarker as measured during the circadian release on a day prior to administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof and the level of the biomarker as measured during the circadian release on the day after administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof. A day prior to administering the compound of Formula (I) applies to a subject that has not previously been administered the compound of Formula (I) within at least the past 24 hours.

[0146] In some embodiments, the circadian release of biomarkers associated with CAH occurs between the hours of 2 a.m. and 10 a.m. In other embodiments, the circadian release of biomarkers associated with CAH occurs between the hours of 6 a.m. and 10 a.m.

[0147] In some embodiments of any of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, is administered to the subject at nighttime or administration prior to sleep (i.e., bedtime administration). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered three to eight hours prior to the circadian release of the biomarker. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered six to eight hours prior to the circadian release of the biomarker. Administration prior to the circadian release may be adapted for shift workers (e.g., those who work at night and sleep during the day), in which case administration will not necessarily occur at nighttime. Administration is therefore dependent upon the expected circadian release of the biomarker, and can vary depending upon the individual's (i.e., subject, patient) particular work and sleep patterns.

[0148] 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 lease 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 of from 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 pre-administration levels.

[0149] 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.

[0150] 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 lease 35%, at least 40%, at least 50%, at least 55% or at least 60% from pre-administration levels. 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%.

[0151] In some embodiments of the methods provided herein, the level of adrenocorticotropic hormone is reduced by an amount of from 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 pre-administration levels.

[0152] In some embodiments, the level of adrenocorticotropic hormone is reduced to a level within the range of adrenocorticotropic hormone expected for a subject without CAH.

[0153] In some embodiments of the methods provided herein, the level of androstenedione is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at lease 35%, at least 40%, at least 50%, at least 55% or at least 60% from pre-administration levels. In some embodiments, the level of androstenedione is reduced by at least 25%. In some embodiments, the level of androstenedione is reduced by at least 30%. In some embodiments, the level of androstenedione is reduced by at least 50%.

[0154] In some embodiments of the methods provided herein, the level of androstenedione is reduced by an amount of from 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 pre-administration levels.

[0155] In some embodiments, the level of androstenedione is reduced to a level within the range of androstenedione expected for a subject without CAH, i.e., less than 200 ng / dL.

[0156] Also provided herein is a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in a subject having 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 biomarker of CAH in a subject, e.g. reduce the androstenedione in the subject. Growth impairment can refer to, e.g., accelerated height velocity, accelerated weight velocity, and / or accelerated bone age.

[0157] Provided herein is a method for reducing the level of one or more biomarkers of congenital adrenal hyperplasia in a subject having 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.

[0158] Provided herein is a method for reducing the dosage of corticosteroid administered to a subject having congenital adrenal hyperplasia for controlling 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.

[0159] Also provided herein is a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject having 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 (see, e.g., Oray, M. et al. (2016): Long-term effect of glucocorticoids, Expert Opinion on Drug Safety. DOI: 10.1517 / 14740338.2016.1140743). Such side effects are associated with every biological system, e.g., musculoskeletal (e.g., osteoporosis, avascular necrosis of bone, and myopathy), endocrine and metabolic (e.g., hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing 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), dermatologic (e.g., dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, and hair loss), neuropsychiatric (e.g., mood changes, depression, euphoria, mood 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 infections, and reactivation of latent infections).

[0160] Accordingly, in some embodiments, the side effects of glucocorticoid treatment are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing 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, dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infections, reactivation of latent infections, and any combination thereof.

[0161] Provided herein is 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 if the level of the one or more biomarkers is elevated compared to a healthy subject not having congenital adrenal hyperplasia; and (iii)administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof if the subject is determined to have elevated levels of the one or more biomarkers.

[0162] In some embodiments, the method further comprises (iv) measuring the level of the one or more biomarkers after administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a biological sample obtained from the subject to determine whether the subject has reduced levels of the one or more biomarkers as compared with the measurement of step (i). In some embodiments, the method further comprises (v) continuing the administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof if the subject has reduced levels of the one or more biomarkers.

[0163] In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject in a similar manner and within a same time of day window. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject within the time of day window from 2 a.m. to 10 a.m. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject within the time of day window from 6 a.m. to 10 a.m.

[0164] 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.

[0165] In some embodiments, steps (i) and (iv) comprise measuring the levels of (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione.

[0166] In some embodiments, step (i) comprises measuring the level of 17-hydroxyprogesterone (17-OHP), wherein the level of 17-hydroxyprogesterone (17-OHP) is elevated when it is greater than or equal to 1,000 ng / dL.

[0167] In some embodiments, step (i) comprises measuring the level of androstenedione, wherein the level of androstenedione is elevated when it is greater than 200 ng / dL.

[0168] In some embodiments of the methods of the present disclosure, the compound of Formula (I) is administered at an amount equivalent to from about 25 mg to about 150 mg of the compound of Formula (I) free base. In some embodiments, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at an amount equivalent to about 50 mg or about 100 mg of the compound of Formula (I) free base.

[0169] In some embodiments of the methods disclosed herein, compound of Formula (I) is administered in the free base form.

[0170] In some embodiments of the methods disclosed herein, the compound of Formula (I) is administered once daily.

[0171] Also provided herein is a method of treating CAH in a pediatric subject. The methods include administering to a pediatric subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering to a pediatric subject a therapeutically effective amount of a SDD of the present disclosure that includes a polymer and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering to a pediatric subject a therapeutically effective amount of pharmaceutical composition of the present disclosure that contains a SDD that includes a polymer and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pediatric subject is a neonate. 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.

[0172] In some embodiments of the methods of the present disclosure, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state. The term "fed state," as used herein, refers to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof from about 1 hour before consumption of food or a nutritional composition to about 1 hour after consumption of food or a nutritional composition. The term "fasted state," as used herein, refers to a gap of at least two hours between consumption of food or a nutritional composition and administration of 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 the subject with food or a nutritional composition, such as a nutritional supplement or formula, a meal replacement beverage, a liquid dietary supplement, or a high caloric liquid meal. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject within about 1 hour before the subject has consumed food or a nutritional composition. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject within about 1 hour after the subject has consumed food or a nutritional composition. Examples of suitable nutritional compositions include, but are not limited to, infant formulas, dietary supplements, dietary substitutes, and rehydration compositions. In some embodiments, the food is a product containing concentrated calories and protein. In some embodiments, the nutritional composition is a composition utilized for enteral and parenteral supplementation for infants, specialty infant formulas, supplements for the elderly, and supplements for those 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 ®< from Ross Products Division, Abbott Laboratories, Columbus, Ohio).

[0173] In some embodiments, the nutritional composition is in liquid form. The energy density of the nutritional compositions, 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 powdered form. When in solid or powdered form, the nutritional supplements can contain from about 1.2 to more than 9 Kcals per gram, such as about 3 to 7 Kcals per gram.

[0174] In some embodiments, the nutritional composition is a meal replacement bar. Examples include PowerBar ®< , Glucerna ®< bars, Choice DM ®< bars, Ensure ®< bars, and Boost ®< bars. In some embodiments, the nutritional composition is a nutrition shake or meal replacement beverage. Commercially available examples include the Ensure ®< branded 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 that contains 1500 calories per liter with a caloric distribution of 14.7% protein, 32% fat and 53.3% carbohydrate.

[0175] 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.

[0176] In some embodiments of the methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject after 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 administration of the nutritional composition. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject at the same time as administration of the nutritional composition.

[0177] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject, followed by administration of the 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, or within a range defined by any of the preceding values after administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. 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, or within a range defined by any of the preceding values after administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the nutritional composition is administered within 30 minutes of administering 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.

[0178] In some embodiments, the nutritional composition is administered to the subject, followed by administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, 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, or within a range defined by any of the preceding values after administration of the nutritional composition. 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, or within a range defined by any of the preceding values after administration of the nutritional composition. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered within 30 minutes of administering 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.

[0179] In some embodiments of the methods, a food effect is observed between administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof in a fed state versus a fasted state. The term "food effect," as used herein, refers to the relative difference in AUC (area under the curve AUC(0-t) and / or AUC (0-∞) ) or C max (maximum plasma concentration or peak plasma concentration) of an active substance, when the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to a subject, concomitantly with food or in a fed state as compared to the same values when the same compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a fasted state. The food effect (F) is calculated as: F% = X fasted − X fed / X fasted × 100 where X fed and X fasted are the values of AUC (AUC (0-t) and / or AUC (0-∞) ) or C max in the fed and fasted state, respectively. In some embodiments, an increased, or positive, food effect is observed when the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state. In some embodiments, administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in an increased, or positive, food effect, whereby an increased C max and / or AUC are observed when administered orally in the fed state as compared to the fasting state.

[0180] In some embodiments of the methods, the ratio of the AUC in the fed state to the 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 the AUC in the fed state to the 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 preceding values. In some embodiments of the methods, the ratio of the AUC in the fed state to the AUC in the fasted state is about 10 to about 20.

[0181] In some embodiments of the methods, the ratio of the AUC in the fed state to the 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 the AUC in the fed state to the AUC in the fasted state is 5, 6, 7, 8, 9, or 10, or within a range defined by any of the preceding values.

[0182] In some embodiments of the methods, the ratio of the C max in the fed state to the C max 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 the C max in the fed state to the C max 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 preceding values. In some embodiments, the mean C max of the compound of Formula (I), or pharmaceutically acceptable salt thereof, is about 1.5 to about 3 times higher in the fed stated compared to the fasted state. In some embodiments of the methods, the ratio of the C max in the fed state to the C max 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 the C max in the fed state to the C max in the fasted state is 5, 6, 7, 8, 9, or 10, or within a range defined by any of the preceding values. In some embodiments, the mean C max of the compound of Formula (I), or pharmaceutically acceptable salt thereof, is 1.5 to 3 times higher in the fed stated compared to the fasted state. In some embodiments, the mean C max of the compound of Formula (I), or pharmaceutically acceptable salt thereof, is about 2 times higher in the fed stated compared to the fasted state. In some embodiments of the methods, the ratio of the C max in the fed state to the C max in the fasted state is about 10 to about 20.

[0183] In some embodiments, 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 with a meal. In some embodiments, the meal is a high fat, high caloric meal. In some embodiments, the meal is a low fat, low caloric meal. In some embodiments, 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 within approximately 5 minutes after the start of the meal. In some embodiments, the meal is an evening meal. In some embodiments, the meal is a morning meal.

[0184] 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 provided draft guidelines regarding high fat and low fat meals ("Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations Guidance for Industry," U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), February 2019, Clinical Pharmacology). Table 1 shows test meal definitions provided by the FDA guidance. Table 1 Meal TypeTotal KcalFatKcalGramsPercentHigh-Fat800-1000500-60055-6550Low-Fat400-500100-12511-1425

[0185] The composition of a high fat meal provided by the FDA guidance is depicted in Table 2. Table 2. Composition of a High Fat Meal* Total Calories800-1000Calories from Protein150Calories from Carbohydrates250Calories from Fat500-600An Example of a High Fat Breakfast• Two eggs fried in butter• Two strips of bacon• Two slices of toast with butter• Four ounces of hash brown potatoes• Eight ounces of whole milk*50 percent of calories are derived from fat. Substitutions can be made to this meal, if the content, volume, and viscosity are maintained.

[0186] The composition of a low fat meal provided by the FDA guidance is depicted in Table 3. Table 3. Composition of a Low Fat Meal Total Calories400-500Fat (g)250Percent Calories from Fat25An Example of a Low Fat Breakfast*• Eight ounces milk (1 percent fat)• One boiled egg• One packet flavored instant oatmeal made with water*This low-fat breakfast contains 387 calories and has 10 grams of fat.

[0187] In some embodiments, a high fat meal contains 800-1000 total Kcal and 500-600 fat Kcal. In some embodiments, a low fat meal contains 400-500 total Kcal and 100-125 fat Kcal.

[0188] Also provided herein is a method of improving gastrointestinal absorption of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in a subject. The method includes orally administering to the subject a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of the compound of Formula (I), or pharmaceutically acceptable salt thereof, which has not been prepared as a spray-dried dispersion. In some embodiments, the subject is a pediatric subject.

[0189] Also provided herein is a method of improving oral bioavailability of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in a subject. The method includes orally administering to the subject a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of the compound of Formula (I), or pharmaceutically acceptable salt thereof, which has not been prepared as a spray-dried dispersion.

[0190] In some embodiments of the methods provided herein, the subject is a pediatric subject.

[0191] Also provided herein is a method of 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 the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a lipidic semi-solid formulation. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is administered to the subject in a fed state.

[0192] Also provided herein is a pharmaceutical composition of the present disclosure for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject. In some embodiments, the subject is in a fed state.

[0193] In some embodiments, the pharmaceutical composition is administered to the subject with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement comprising about 1000 to about 2000 calories per liter with a fat content greater than about 30%. In some embodiments, the nutritional composition is a liquid dietary supplement comprising 1500 calories per liter with a caloric distribution of 14.7% protein, 32% fat and 53.3% carbohydrate. 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 administration of the pharmaceutical composition.

[0194] In some embodiments, the pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is measured in terms of C max , AUC, or a combination thereof of a compound of Formula (I) when comparing oral administration of the pharmaceutical composition in the fed and fasting states. 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 C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is about 10 to about 20. 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 C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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 1.5 to about 3. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is 1 to 4 or 5 to 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 1 to 4. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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 1.5 to 3. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is 1.5 to 3.

[0195] In some embodiments, the subject is a pediatric subject.

[0196] 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 ratio of the AUC in the fed state to the AUC in the fasted state of about 5 to about 10. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of about 5 to about 10. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of about 10 to about 20. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of about 10 to about 20. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the 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 the C max in the fed state to the C max 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 the AUC in the fed state to the AUC in the fasted state of about 1 to about 4. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of about 1 to about 4. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of about 1.5 to about 3. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of about 1.5 to about 3. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the 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 the C max in the fed state to the C max in the fasted state of 1 to 4 or 5 to 10. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of 1 to 4. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of 1 to 4. In some embodiments, the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of 1.5 to 3. In some embodiments, the compound of Formula (I) has a ratio of the C max in the fed state to the C max in the fasted state of 1.5 to 3.

[0197] In some embodiments, the pharmaceutical composition is administered to the 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 the start of the meal. In some embodiments, the meal is an evening meal. In some embodiments, the meal is a morning meal.

[0198] In some embodiments, administering the pharmaceutical composition exhibits a positive food effect. In some embodiments, the positive food effect is measured in terms of C max , AUC, or combinations thereof of the compound of Formula (I) when comparing oral administration of the pharmaceutical composition in the fed and fasting states. 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 C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is about 10 to about 20. 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 C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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 1.5 to about 3. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is 1 to 4 or 5 to 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 1 to 4. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max 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 1.5 to 3. In some embodiments, the ratio of the C max of the compound of Formula (I) in the fed state to the C max of the compound of Formula (I) in the fasted state is 1.5 to 3.

[0199] For the avoidance of doubt, also provided herein is the corresponding compound of Formula (I), or a pharmaceutically acceptable salt thereof, or corresponding pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the corresponding methods, as described herein.

[0200] For the avoidance of doubt, also provided herein is use of the corresponding compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the corresponding methods, as described herein.

[0201] For the avoidance of doubt, also provided herein is use of the 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, as described herein.Reduction in glucocorticoid burden, adrenal androgens and precursors

[0202] Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. In some embodiments, the subject is concurrently receiving a dose of a 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.

[0203] In some embodiments, the glucocorticoid dose is measured in hydrocortisone equivalents. In some embodiments, the glucocorticoid dose is measured as a multiple of the upper limit of normal of physiologic dosing in hydrocortisone equivalents. Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing.

[0204] In some embodiments, the glucocorticoid dose is a physiologic dose as measured after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose of about 4 to about 12 mg / m 2< / day as measured after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose of about 4 to about 9 mg / m 2< / day as measured after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose that is less than about 8 mg / m 2< / day as measured after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the glucocorticoid dose is a physiologic dose as measured after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose of about 4 to about 12 mg / m 2< / day as measured after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose of about 4 to about 9 mg / m 2< / day as measured after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is a physiologic dose that is less than about 8 mg / m 2< / day as measured after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the glucocorticoid dose concurrently given to the subject is a normal physiological dose of hydrocortisone equivalents. In some embodiments, the glucocorticoid dose concurrently given to the subject is determined after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose concurrently given to the subject is determined after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 2 to about 16 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 4 to about 12 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 5 to about 11 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 6 to about 10 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 7 to about 9 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 4 to about 9 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 8 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is about 12 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is less than about 8 mg / m 2< / day. In some embodiments, a normal physiological dose of hydrocortisone equivalents is 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.

[0207] In some embodiments, the glucocorticoid dose concurrently given to the subject is at the upper limit of normal of a normal physiological dose of hydrocortisone equivalents. In some embodiments, the glucocorticoid dose concurrently given to the subject is determined after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose concurrently given to the subject is determined after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the upper limit of normal is 1.5 times the normal physiological dose. In some embodiments, the upper limit of normal is about 1.5 times the normal physiological dose. In some embodiments, the upper limit of normal is about 1.5 times the normal physiological dose. In some embodiments, the upper limit of normal is about 2 times the normal physiological dose. In some embodiments, the upper limit of normal is about 2.5 times the normal physiological dose. In some embodiments, the upper limit of normal 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 preceding values.

[0208] In some embodiments, the glucocorticoid dose of the subject is reduced by about 10% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 20% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 30% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 40% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 50% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 60% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 70% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by less than about 20% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 20% to about 50% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by greater than about 50% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the glucocorticoid dose of the subject is reduced by about 10% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 20% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 30% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 40% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 60% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 70% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by less than about 20% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by about 20% to about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose of the subject is reduced by greater than about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the glucocorticoid dose of the subject is reduced within a range defined by any of the preceding values.

[0211] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 25% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the 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 time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the 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 time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is within normal limits after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the pharmaceutical composition comprising the 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 time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the pharmaceutical composition comprising the 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 time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the level of 17-hydroxyprogesterone of the subject is reduced within a range defined by any of the preceding values.

[0214] In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 25% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the 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 time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the 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 time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is less than 1.5 times the upper limit of normal after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is within normal limits after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the level of adrenocorticotropic hormone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising the 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 time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising the 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 time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of adrenocorticotropic hormone is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the level of adrenocorticotropic hormone of the subject is reduced within a range defined by any of the preceding values.

[0217] In some embodiments, the level of androstenedione is reduced by at least 25% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is reduced by at least 30% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is reduced by at least 50% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is less than 1.5 times the upper limit of normal after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is within normal limits after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the level of androstenedione is reduced by at least about 25% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is reduced by at least about 30% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is reduced by at least about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of androstenedione is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the level of androstenedione of the subject is reduced within a range defined by any of the preceding values.

[0220] In some embodiments, the level of testosterone is reduced by at least 25% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is reduced by at least 30% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is reduced by at least 50% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is less than 1.5 times the upper limit of normal after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is within normal limits after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the level of testosterone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is reduced by at least about 30% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is reduced by at least about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of testosterone is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the level of testosterone of the subject is reduced within a range defined by any of the preceding values.

[0223] 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% after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone and the level of androstenedione is relative to the level of 17-hydroxyprogesterone and the level of androstenedione prior to administration of the 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 and the level of androstenedione is less than 1.5 times the upper limit of normal after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least about 50% and the level of androstenedione is reduced by at least about 50% after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of the level of 17-hydroxyprogesterone and the level of androstenedione is relative to the level of 17-hydroxyprogesterone and the level of androstenedione prior to administration of the pharmaceutical composition comprising the 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 and the level of androstenedione is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the level of 17-hydroxyprogesterone and androstenedione of the subject is reduced within a range defined by any of the preceding values.

[0226] In some embodiments, the subject exhibits a decrease in glucocorticoid burden after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility, is improved after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the subject exhibits a decrease in glucocorticoid burden after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility, is improved after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the quality of life as measured by the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) in the subject is improved after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the improvement in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) is relative to the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) results prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, fatigue is reduced in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction in fatigue is relative to the fatigue prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, sleep is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in sleep is relative to the sleep prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, insulin resistance is reduced in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction of insulin resistance is relative to the insulin resistance prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, glucose tolerance is reduced in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction in glucose tolerance is relative to the glucose tolerance prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, glucose control is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in glucose control is relative to the glucose control prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, lipid levels reflecting dyslipidemia are reduced in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction in lipid levels is relative to the lipid levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, lipid levels reflecting hyperlipidemia are reduced in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the reduction in lipid levels is relative to the lipid levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, bone mineral density is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in bone mineral density is relative to the bone mineral density prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, bone turnover is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in bone turnover is relative to the bone turnover prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, fat mass is decreased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease in fat mass is relative to the fat mass prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, body weight is decreased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease in body weight is relative to the body weight prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, central obesity is decreased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease in central obesity is relative to the central obesity prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, blood pressure is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in blood pressure is relative to the blood pressure prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the severity of hirsutism is decreased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the decrease 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.

[0243] In some embodiments, menstrual cyclicity is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in menstrual cyclicity is relative to the menstrual cyclicity prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, control of testicular adrenal rest tumor is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in control of testicular adrenal rest tumor is relative to the control of testicular adrenal rest tumor prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, fertility is increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in fertility is relative to the fertility prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, gonadotropin levels are increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in gonadotropin levels is relative to the gonadotropin levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, progesterone levels are increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in progesterone levels is relative to the progesterone levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, semen levels are increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in semen levels is relative to the semen levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, LH (luteinizing hormone) levels are increased in the subject after a time period of administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the increase in LH levels are relative to the LH levels prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the time period of administration is at least about 4 weeks. In some embodiments, the time period of administration is at least about 24 weeks. In some embodiments, the time period of administration is at least about one year. In some embodiments, the time period of administration is at least 4 weeks. In some embodiments, the time period of administration is at least 24 weeks. In some embodiments, the time period of administration is at least one year. In some embodiments, the time period of administration is less than about 1 day. In some embodiments, the time period of administration is about 1, 2, 3, 4, 5, 6 or 7 days, or within a range of any of the preceding values. In some embodiments, the time period of administration 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 a range of any of the preceding values. In some embodiments, the time period of administration is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or within a range of any of the preceding values. It is understood that comparative measurements occur preferably during the morning.

[0251] In some embodiments, the subject is a pediatric subject. In some embodiments, the pediatric subject is less than or equal to six years old. In some embodiments, the pediatric subject is greater than six years old and less than eleven years old. In some embodiments, the pediatric subject is greater than ten years old and less than fifteen years old. In some embodiments, the pediatric subject is greater than fourteen years old and less than nineteen years old.

[0252] In some embodiments, the subject is an adult subject. In some embodiments, the subject is over eighteen years old. In some embodiments, the subject is female. In some embodiments, the subject is male.

[0253] 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 hydrochloric acid salt or p-toluenesulfonic acid salt.

[0254] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a p-toluenesulfonic acid salt described herein.

[0255] For the avoidance of doubt, also provided herein is the corresponding compound of Formula (I), or a pharmaceutically acceptable salt thereof, or corresponding pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the corresponding methods, as described herein.

[0256] For the avoidance of doubt, also provided herein is use of the corresponding compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the corresponding methods, as described herein.

[0257] For the avoidance of doubt, also provided herein is use of the 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, as described herein.p-Toluenesulfonic Acid Salt

[0258] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof 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, p-toluenesulfonic acid salt.

[0259] In some embodiments, 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, p-toluenesulfonic acid salt is a crystalline salt. In some embodiments, the p-toluenesulfonic acid crystalline salt has Form 1.

[0260] In some embodiments, the p-toluenesulfonic acid crystalline salt has an X-ray powder diffraction pattern as substantially shown in Figure 27. In some embodiments, the p-toluenesulfonic acid crystalline salt has a DSC thermogram substantially as depicted in Figure 28. In some embodiments, the p-toluenesulfonic acid crystalline salt has a thermogravimetric analysis (TGA) thermogram substantially as depicted in Figure 28.

[0261] In some embodiments, the p-toluenesulfonic acid crystalline salt has at least one X-ray powder diffraction (XRPD) peak, in terms of 2-theta (± 0.2 degrees), selected 9.1, 11.3, 13.2, 16.3 and 21.1 degrees. In some embodiments, the p-toluenesulfonic acid crystalline salt has at least two X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (± 0.2 degrees), selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees. In some embodiments, the p-toluenesulfonic acid crystalline salt has at least three X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (± 0.2 degrees), selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees. In some embodiments, the p-toluenesulfonic acid crystalline salt has at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (± 0.2 degrees), selected from 9.1, 11.3, 13.2, 16.3 and 21.1 degrees. In some embodiments, the p-toluenesulfonic acid crystalline salt has characteristic X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (± 0.2 degrees), at 9.1, 11.3, 13.2, 16.3 and 21.1 degrees. In some embodiments, the p-toluenesulfonic acid crystalline salt has an endothermic peak having an onset of melt at about 156 °C (22.2 J / g) in a differential scanning calorimetry (DSC) thermogram.Lipidic Semi-Solid Formulation

[0262] Provided herein is a lipidic semi-solid formulation, which is a pharmaceutical composition comprising: (a) a compound of Formula (I): or a pharmaceutically acceptable salt thereof; and (b) one or more of an oily phase vehicle, an emulsifying agent, a nonionic surfactant, and a solubilizing agent.

[0263] In some embodiments, the pharmaceutical composition comprises about 1 wt% to about 20 wt% 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 wt% to about 15 wt% 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 wt% 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 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or within a range of any of the preceding values.

[0264] In some embodiments, the pharmaceutical composition comprises an oily phase vehicle. An oily phase vehicle is a solvent that is poorly miscible with water. In some embodiments, the pharmaceutical composition comprises about 1 wt% to about 50 wt% of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 20 wt% to about 50 wt% of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35 wt% to about 45 wt% of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 39 wt% of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 wt% of the oily phase vehicle, or within a range of any of the preceding values.

[0265] In some embodiments, the oily 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 oily phase vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides are Labrafac TM Lipophile WL1349. In some embodiments, the medium-chain triglycerides are Miglyol 812N.

[0266] In some embodiments, the pharmaceutical composition comprises an emulsifying agent. An emulsifying agent is a compound or substance that acts as a stabilizer for emulsions. In some embodiments, the pharmaceutical composition comprises about 5 wt% to about 50 wt% of the emulsifying agent. In some embodiments, the pharmaceutical composition comprises about 10 wt% to about 30 wt% of the emulsifying agent. In some embodiments, the pharmaceutical composition comprises about 15 wt% to about 25 wt% of the emulsifying agent. In some embodiments, the pharmaceutical composition comprises about 20 wt% of the emulsifying agent. 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 wt% of the emulsifying agent, or within a range of any of the preceding values.

[0267] In some embodiments, the emulsifying agent is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the emulsifying agent is propylene glycol dicaprylate / dicaprate. In some embodiments, the propylene glycol dicaprylate / dicaprate is Labrafac TM PG.

[0268] In some embodiments, the pharmaceutical composition comprises a nonionic surfactant. A nonionic surfactant is a substance with a hydrophilic head and a hydrophobic tail that has no charge that is a formulation component added to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition comprises about 5 wt% to about 50 wt% of the nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 10 wt% to about 30 wt% of the nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 15 wt% to about 25 wt% of the nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 19 wt% of the 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 wt% of the nonionic surfactant, or within a range of any of the preceding values.

[0269] In some embodiments, the nonionic surfactant is selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, Gelucire, lauroyl polyoxyl-32 glycerides, Poloxamer, PEG-32 stearate, and PEG-32 hydrogenated palm glycerides. In some embodiments, the nonionic surfactant is lauroyl polyoxyl-32 glycerides. In some embodiments, the lauroyl polyoxyl-32 glycerides are Gelucire ®< 44 / 14.

[0270] In some embodiments, the pharmaceutical composition comprises a solubilizing agent. A solubilizing agent is a solvent that assists with solubilizing the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1 wt% to about 50 wt% of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 1 wt% to about 20 wt% of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 5 wt% to about 15 wt% of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 11 wt% 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 wt% of the solubilizing agent, or within a range of any of the preceding values.

[0271] In some embodiments, the solubilizing agent is selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glycerides, 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.

[0272] 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) an oily phase vehicle; (c) an emulsifying agent; (d) a nonionic surfactant; and (e) a solubilizing agent.

[0273] In some embodiments, the pharmaceutical composition comprises: (a) about 5 wt% to about 15 wt% 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 35 wt% to about 45 wt% of an oily phase vehicle; (c) about 15 wt% to about 25 wt% of an emulsifying agent; (d) about 15 wt% to about 25 wt% of a nonionic surfactant; and (e) about 5 wt% to about 15 wt% of a solubilizing agent.

[0274] In some embodiments, the pharmaceutical composition comprises: (a) about 10 wt% 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 39 wt% of an oily phase vehicle; (c) about 20 wt% of an emulsifying agent; (d) about 19 wt% of a nonionic surfactant; and (e) about 11 wt% of a solubilizing agent.

[0275] 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) a medium-chain triglycerides component; (c) a propylene glycol dicaprylate / dicaprate component; (d) a lauroyl polyoxyl-32 glycerides component; and (e) a vitamin E polyethylene glycol succinate component.

[0276] In some embodiments, the pharmaceutical composition comprises: (a) about 5 wt% to about 15 wt% 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 wt% to about 45 wt% of medium-chain triglycerides; (c) about 15 wt% to about 25 wt% of propylene glycol dicaprylate / dicaprate; (d) about 15 wt% to about 25 wt% of lauroyl polyoxyl-32 glycerides; and (e) about 5 wt% to about 15 wt% of vitamin E polyethylene glycol succinate.

[0277] In some embodiments, the pharmaceutical composition comprises: (a) about 10 wt% 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 39 wt% of medium-chain triglycerides; (c) about 20 wt% of propylene glycol dicaprylate / dicaprate; (d) about 19 wt% of lauroyl polyoxyl-32 glycerides; and (e) about 11 wt% of vitamin E polyethylene glycol succinate.

[0278] In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity between about 15 to about 40 centipoise at about 45 °C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity between about 26 to about 30 centipoise at about 45 °C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity between about 5 to about 25 centipoise at about 60 °C. In some embodiments, the lipidic semi-solid pharmaceutical composition has a viscosity between about 14 to about 18 centipoise at about 60 °C.

[0279] In some embodiments, the pharmaceutical composition does not comprise a combination of mannitol, croscarmellose sodium, maize starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0280] In some embodiments, the pharmaceutical composition does not comprise at least one of mannitol, croscarmellose sodium, maize starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0281] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or pharmaceutically acceptable salt thereof, in crystalline form. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or pharmaceutically acceptable salt thereof, in amorphous form. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) as a free base. In some embodiments, the crystalline form of the compound of Formula (I) is of Form I.

[0282] In some embodiments, the pharmaceutical composition is 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, 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.

[0283] In some embodiments, the pharmaceutical composition is in the form of a tablet, capsule, sachet, powder, granules, coated particle, coated tablet, enterocoated tablet, enterocoated capsule, melting strip, or melting 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.

[0284] Some embodiments provide a method for preparing the pharmaceutical composition, comprising: (a) heating a mixture of an oily phase vehicle, an emulsifying agent, a nonionic surfactant, and a solubilizing agent; (b) mixing the mixture of step (a) until a homogeneous mixture is achieved; and (c) mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof, with the homogeneous mixture of step (b) until the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is dissolved, forming a composition.

[0285] In some embodiments, the method further comprises: (d) encapsulating the composition of step (c) in a capsule shell to form a capsule; and (e) banding the capsule of step (d) in a mixture of banding agent and banding solvent. Liquid Formulations

[0286] Provided herein is a pharmaceutical composition in oral solution dosage form comprising: (a) a compound of Formula (I): or a pharmaceutically acceptable salt thereof; (b) one or more of a sweetener, an anti-oxidant, and a flavor; and (c) a liquid vehicle.

[0287] 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 a range of any of the preceding values.

[0288] 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 the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1 w / v% to about 0.5 w / v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.15 w / v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5 w / v% of the sweetener, or within a range of any of the preceding values.

[0289] In some embodiments, the sweetener is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame. In some embodiments, the sweetener is saccharin.

[0290] In some embodiments, the pharmaceutical composition comprises an anti-oxidant. An anti-oxidant is a formulation component included to improve stability by preventing oxidation. In some embodiments, the pharmaceutical composition comprises about 0.01 w / v% to about 1.5 w / v% of the anti-oxidant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / v% to about 0.5 w / v% of the anti-oxidant. In some embodiments, the pharmaceutical composition comprises about 0.17 w / v% of the anti-oxidant. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5 w / v% of the anti-oxidant, or within a range of any of the preceding values.

[0291] In some embodiments, the anti-oxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone, and citric acid. In some embodiments, the anti-oxidant is butylated hydroxytoluene.

[0292] In some embodiments, the pharmaceutical composition comprises a flavor. A flavor is a formulation component added to mask taste through aromatics. In some embodiments, the pharmaceutical composition comprises about 0.01 w / v% to about 0.5 w / v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.05 w / v% to about 0.2 w / v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.10 w / v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2 w / v% of the flavor, or within a range of any of the preceding values.

[0293] In some embodiments, 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. In some embodiments, the flavor is FONA orange flavor.

[0294] A liquid vehicle is a solvent capable of dissolving or partially dissolving the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the purposes of delivery as an oral dosing solution. In some embodiments, the pharmaceutical composition comprises about 50 w / v% to about 99.9 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 90 w / v% to about 99 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 92 w / v% to about 97 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 94.6 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 w / v% of the liquid vehicle, or within a range of any of the preceding values.

[0295] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the liquid vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides is Labrafac Lipophile WL1349.

[0296] In some embodiments, the pharmaceutical composition further comprises a surfactant. A surfactant is a formulation component added to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition comprises about 1 w / v% to about 50 w / v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 10 w / v% to about 30 w / v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 20 w / v% of the 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 w / v% of the surfactant, or within a range of any of the preceding values.

[0297] In some embodiments, the surfactant is selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glycerides, sodium lauryl sulfate, Poloxamer, corn oil PEG-6 esters, and hydrogenated palm / palm kernel oil PEG-6 esters. In some embodiments, the surfactant is oleoyl polyoxyl-6 glycerides. In some embodiments, the oleoyl polyoxyl-6 glycerides is LABRAFIL M 1944 CS.

[0298] In some embodiments, the pharmaceutical composition comprises about 50 w / v% to about 90 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 70 w / v% to about 80 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 75 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 74.6 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 w / v% of the liquid vehicle, or within a range of any of the preceding values.

[0299] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the liquid vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides is Labrafac Lipophile WL1349.

[0300] 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) a sweetener; (c) an anti-oxidant; (d) a flavor; and (e) a liquid vehicle.

[0301] In some embodiments, the pharmaceutical composition further comprises a surfactant.

[0302] In some embodiments, the pharmaceutical composition comprises: (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% of an anti-oxidant; (d) about 0.05 w / v% to about 0.2 w / v% of a flavor; and (e) about 92 w / v% to about 97 w / v% of a liquid vehicle.

[0303] In some embodiments, the pharmaceutical composition comprises: (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% of a sweetener; (c) about 0.17 w / v% of an anti-oxidant; (d) about 0.1 w / v% of a flavor; and (e) about 94.6 w / v% of a liquid vehicle.

[0304] In some embodiments, the pharmaceutical composition comprises: (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% of an anti-oxidant; (d) about 0.05 w / v% to about 0.2 w / v% of a flavor; (e) about 15 w / v% to about 25 w / v% of a surfactant; and (f) about 70 w / v% to about 80 w / v% of a liquid vehicle.

[0305] In some embodiments, the pharmaceutical composition comprises: (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% of a sweetener; (c) about 0.17 w / v% of an anti-oxidant; (d) about 0.1 w / v% of a flavor; (e) about 20 w / v% of a surfactant; and (f) about 75 w / v% of a liquid vehicle.

[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) saccharin; (c) butylated hydroxytoluene; (d) FONA orange flavor; and (e) medium-chain triglycerides.

[0307] In some embodiments, the pharmaceutical composition further comprises oleoyl polyoxyl-6 glycerides.

[0308] In some embodiments, the pharmaceutical composition comprises: (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 saccharin; (c) about 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene; (d) about 0.05 w / v% to about 0.2 w / v% of FONA orange flavor; and (e) about 92 w / v% to about 97 w / v% of medium-chain triglycerides.

[0309] In some embodiments, the pharmaceutical composition comprises: (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% of saccharin; (c) about 0.17 w / v% of butylated hydroxytoluene; (d) about 0.1 w / v% of FONA orange flavor; and (e) about 94.6 w / v% of medium-chain triglycerides.

[0310] In some embodiments, the pharmaceutical composition comprises: (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 saccharin; (c) about 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene; (d) about 0.05 w / v% to about 0.2 w / v% of FONA orange flavor; (e) about 15 w / v% to about 25 w / v% of oleoyl polyoxyl-6 glycerides; and (f) about 70 w / v% to about 80 w / v% of medium-chain triglycerides.

[0311] In some embodiments, the pharmaceutical composition comprises: (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% of saccharin; (c) about 0.17 w / v% of butylated hydroxytoluene; (d) about 0.1 w / v% of FONA orange flavor; (e) about 20 w / v% of oleoyl polyoxyl-6 glycerides; and (f) about 75 w / v% of medium-chain triglycerides.

[0312] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I) as a free base.

[0313] In some embodiments, the pharmaceutical composition is 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 / mL to about 200 mg / mL, 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 / mL to about 150 mg / mL, 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 / mL, 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 / mL, based on the weight of the free base.

[0314] In some embodiments, the liquid pharmaceutical composition has a viscosity between about 1 to about 50 centipoise at about 25 °C.

[0315] Some embodiments provide a method for preparing a pharmaceutical composition comprising: (a) mixing a liquid vehicle with a sweetener; (b) mixing the mixture of step (a) with an anti-oxidant and a flavor; (c) mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof, with the mixture of step (b); and (d) mixing the mixture of step (c) with an additional portion of the liquid vehicle.

[0316] In some embodiments, step (a) of the method comprises mixing a liquid vehicle with a sweetener and a surfactant.Spray-dried dispersions

[0317] The methods and uses of the present disclosure may comprise administering a spray-dried dispersion (SDDs) 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 to the use of the SDDs in the treatment of congenital adrenal hyperplasia (CAH).

[0318] In some embodiments, concentration and bioavailability enhancement in an aqueous environment of a low-solubility drug in a spray-dried dispersion is achieved if the SDD exhibits one or more properties, including, for example: (1) the solid dispersion is substantially homogeneous; (2) the drug is substantially amorphous; (3) the SDD has a relatively high drug loading; and (4) the SDD has a low residual solvent content. In some embodiments, the dispersion, when administered to an aqueous environment, provides at least a temporary dissolved drug concentration in the aqueous environment that is greater than the solubility of the crystalline form of the drug in the same environment. The aqueous environment can be, for example, an in vitro environment, such as a dissolution test media (e.g., phosphate buffered saline (PBS) solution), or an in vivo environment, such as the gastrointestinal (GI) tract of an animal, for example, a human. In some embodiments, the aqueous environment is the lower GI tract, such as the small intestine and large intestine.

[0319] Provided in the present disclosure is a spray-dried dispersion that contains a polymer and a compound having the structure of Formula (I): or a pharmaceutically acceptable salt thereof. In some embodiments, the SDD includes a polymer selected from a neutral polymer, an enteric polymer, and a pyrrolidone polymer. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is from about 1:1 to about 1:9.

[0320] In some embodiments, the polymer is a neutral polymer. For example, the polymer does not contain any charged functional groups. In some embodiments, the neutral polymer is a cellulosic polymer. For example, the cellulosic polymer can be a polymer with at least one ester- and / or ether-linked substituent in which the polymer has a degree of substitution of at least 0.05 for each substituent. Examples of suitable neutral polymers include, but are not limited to, hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC).

[0321] In some embodiments, the polymer is an enteric polymer. An "enteric polymer," as used herein, is a polymeric substance that is substantially insoluble and / or substantially stable under acidic conditions exhibiting a pH of less than about 7 and which is substantially soluble or can decompose under conditions exhibiting a pH of about 7 or more. Examples of suitable enteric polymers include, but are not limited to, carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetal phthalate, a copolymer of vinyl acetate / maleic anhydride, a copolymer of vinylbutylether / maleic anhydride, a copolymer of styrene / maleic acid monoester, a copolymer of methyl acrylate / methacrylic acid, a copolymer of styrene / acrylic acid, a copolymer of methyl acrylate / methacrylic acid / octyl acrylate, a copolymer of methacrylic acid / methyl methacrylate, an amino methacrylate copolymer, an ammonioalkyl methacrylate copolymer, a methacrylic copolymer, and mixtures thereof. In some embodiments, the enteric polymer is selected from hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), an amino methacrylate copolymer, an ammonioalkyl methacrylate copolymer, and a methacrylic copolymer. In some embodiments, the enteric polymer is a Eudragit ®< polymer sold by Evonik Industries (Essen, Germany). In some embodiments, the enteric polymer is an amino methacrylate copolymer. In some embodiments, the amino methacrylate copolymer is Eudragit ®< E PO / 100. In some embodiments, the enteric polymer is an ammonioalkyl methacrylate copolymer. In some embodiments, the ammonioalkyl methacrylate copolymer is Eudragit ®< RLPO. In some embodiments, the enteric polymer is a methacrylic copolymer. In some embodiments, the methacrylic copolymer is Eudragit ®< L100 or Eudragit ®< S100.

[0322] In some embodiments, the polymer is a pyrrolidone polymer. For example, the pyrrolidone polymer can be a vinyl pyrrolidone polymer, such as polyvinyl pyrrolidone (PVP) or polyvinyl pyrrolidone vinyl acetate (PVP / VA), including homopolymers and copolymers of PVP and homopolymers and copolymers of N-vinyl pyrrolidone. In some embodiments, the pyrrolidone polymer is PVP / VA. In some embodiments, the PVP / VA is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate. In some embodiments, the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 30:70 to about 70:30 by weight, such as about 40:60 to about 60:40 by weight, or about 45:55 to about 55:45 by weight. In some embodiments, the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 30:70, about 35:65, about 40:60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, or about 70:30 by weight. In some embodiments, the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 60:40 by weight.

[0323] In some embodiments, the pyrrolidone polymer has the structure: where the value of n is about 1 to about 2 times the value of m. For example, the value of n can be about 1, about 1.05, about 1.1, about 1.15, about 1.16, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.55, about 1.6, about 1.65, about 1.7, about 1.75, about 1.8, about 1.85, about 1.9, about 1.95, or about 2 times the value of m, or a value within a range defined by any of the preceding values. In some embodiments, the value of n is about 1.16 times the value of m. In some embodiments, the copolymer is copovidone, and the value of n is about 1.16 times the value of m.

[0324] In some embodiments, the pyrrolidone polymer has the structure: where the value of n is 1 to 2 times the value of m. For example, the value of n can be 1, 1.05, 1.1, 1.15, 1.16, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, or 2 times the value of m, or a value within a range defined by any of the preceding values. In some embodiments, the value of n is 1.16 times the value of m. In some embodiments, the copolymer is copovidone, and the value of n is 1.16 times the value of m.

[0325] In some embodiments, the polymer used in the disclosed SDDs is present in an amount sufficient to increase the maximum drug concentration of the amorphous form of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the environment of use (e.g., aqueous environment) relative to a control composition that contains an equivalent amount of a crystalline form of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, but without polymer. In some embodiments, once the SDD is introduced into an environment of use (e.g., aqueous environment), the polymer increases the aqueous concentration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, relative to the control composition. It is to be understood that the control composition is free from solubilizers or other components that would materially affect the solubility of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in solid form in the control composition.

[0326] In some embodiments of the SDDs, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is from about 1:1 to about 1:9. For example, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer can be about 1:1 to about 1:8, about 1:1 to about 1:7, about 1:1 to about 1:6, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about 1:1 to about 1:2, about 1:1 to about 1:1.5, about 1:1.5 to about 1:9, or about 1:2.5 to about 1:4. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is about 1:9, about 1:8, about 1:7.5, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2.5, about 1:2, about 1:1.5, or about 1:1, or a weight ratio within a range defined by any of the preceding values. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is about 1:9. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is about 1:1.5. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is about 1:1.

[0327] In some embodiments of the SDDs, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is from 1:1 to 1:9. For example, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer can be 1:1 to 1:8, 1:1 to 1:7, 1:1 to 1:6, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:1 to 1:1.5, 1:1.5 to 1:9, or 1:2.5 to 1:4. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is 1:9, 1:8,1:7.5,1:7,1:6,1:5,1:4,1:3,1:2.5, 1:2, 1:1.5, or 1:1, or a weight ratio within a range defined by any of the preceding values. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is 1:9. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is 1:1.5. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the polymer is 1:1.

[0328] In some embodiments, the spray dried dispersion includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer that is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the structure: where the value of n is about 1 to about 2 times the value of m and the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 60:40 by weight, and the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the copolymer is from about 1:1 to about 1:9.

[0329] In some embodiments, the spray dried dispersion includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer that is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the structure: where the value of n is 1 to 2 times the value of m and the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of 60:40 by weight, and the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the copolymer is from 1:1 to 1:9.

[0330] In some embodiments of the SDDs, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer together form homogeneous particles. In some embodiments, the particles are a substantially homogeneous composition that includes the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer. As used herein, "substantially homogeneous" means that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is dispersed as homogeneously as possible throughout the polymer and can be thought of as a solid solution of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, dispersed in the polymer. While the dispersion can have some concentrated domains of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the dispersion itself has a single glass transition temperature (T g ) which demonstrates that the dispersion is substantially homogeneous. This contrasts with a simple physical mixture of pure amorphous particles of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and pure amorphous polymer particles, which generally displays two distinct T g S, one of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one of the polymer. "T g ," as used herein, is the characteristic temperature where a glassy material, upon gradual heating, undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glass state to a rubber state.

[0331] In some embodiments, the particles have a particle size distribution (D-value, D 50 ), of about 5 µm to about 100 µm, such as about 5 µm to about 95 µm, about 5 µm to about 90 µm, about 5 µm to about 85 µm, about 5 µm to about 80 µm, about 5 µm to about 75 µm, about 5 µm to about 70 µm, about 5 µm to about 65 µm, about 5 µm to about 60 µm, about 5 µm to about 55 µm, about 5 µm to about 50 µm, about 5 µm to about 45 µm, about 5 µm to about 40 µm, about 5 µm to about 35 µm, about 5 µm to about 30 µm, about 5 µm to about 25 µm, about 5 µm to about 20 µm, about 5 µm to about 15 µm, about 5 µm to about 10 µm, about 10 µm to about 100 µm, about 10 µm to about 95 µm, about 10 µm to about 90 µm, about 10 µm to about 85 µm, about 10 µm to about 80 µm, about 10 µm to about 75 µm, about 10 µm to about 70 µm, about 10 µm to about 65 µm, about 10 µm to about 60 µm, about 10 µm to about 55 µm, about 10 µm to about 50 µm, about 10 µm to about 45 µm, about 10 µm to about 40 µm, about 10 µm to about 35 µm, about 10 µm to about 30 µm, about 10 µm to about 25 µm, about 10 µm to about 20 µm, about 10 µm to about 15 µm, about 15 µm to about 100 µm, about 15 µm to about 95 µm, about 15 µm to about 90 µm, about 15 µm to about 85 µm, about 15 µm to about 80 µm, about 15 µm to about 75 µm, about 15 µm to about 70 µm, about 15 µm to about 65 µm, about 15 µm to about 60 µm, about 15 µm to about 55 µm, about 15 µm to about 50 µm, about 15 µm to about 45 µm, about 15 µm to about 40 µm, about 15 µm to about 35 µm, about 15 µm to about 30 µm, about 15 µm to about 25 µm, about 15 µm to about 20 µm, about 20 µm to about 100 µm, about 20 µm to about 95 µm, about 20 µm to about 90 µm, about 20 µm to about 85 µm, about 20 µm to about 80 µm, about 20 µm to about 75 µm, about 20 µm to about 70 µm, about 20 µm to about 65 µm, about 20 µm to about 60 µm, about 20 µm to about 55 µm, about 20 µm to about 50 µm, about 20 µm to about 45 µm, about 20 µm to about 40 µm, about 20 µm to about 35 µm, about 20 µm to about 30 µm, about 20 µm to about 25 µm, about 25 µm to about 100 µm, about 25 µm to about 95 µm, about 25 µm to about 90 µm, about 25 µm to about 85 µm, about 25 µm to about 80 µm, about 25 µm to about 75 µm, about 25 µm to about 70 µm, about 25 µm to about 65 µm, about 25 µm to about 60 µm, about 25 µm to about 55 µm, about 25 µm to about 50 µm, about 25 µm to about 45 µm, about 25 µm to about 40 µm, about 25 µm to about 35 µm, about 25 µm to about 30 µm, about 30 µm to about 100 µm, about 30 µm to about 95 µm, about 30 µm to about 90 µm, about 30 µm to about 85 µm, about 30 µm to about 80 µm, about 30 µm to about 75 µm, about 30 µm to about 70 µm, about 30 µm to about 65 µm, about 30 µm to about 60 µm, about 30 µm to about 55 µm, about 30 µm to about 50 µm, about 30 µm to about 45 µm, about 30 µm to about 40 µm, about 30 µm to about 35 µm, about 35 µm to about 100 µm, about 35 µm to about 95 µm, about 35 µm to about 90 µm, about 35 µm to about 85 µm, about 35 µm to about 80 µm, about 35 µm to about 75 µm, about 35 µm to about 70 µm, about 35 µm to about 65 µm, about 35 µm to about 60 µm, about 35 µm to about 55 µm, about 35 µm to about 50 µm, about 35 µm to about 45 µm, about 35 µm to about 40 µm, about 40 µm to about 100 µm, about 40 µm to about 95 µm, about 40 µm to about 90 µm, about 40 µm to about 85 µm, about 40 µm to about 80 µm, about 40 µm to about 75 µm, about 40 µm to about 70 µm, about 40 µm to about 65 µm, about 40 µm to about 60 µm, about 40 µm to about 55 µm, about 40 µm to about 50 µm, about 40 µm to about 45 µm, about 45 µm to about 100 µm, about 45 µm to about 95 µm, about 45 µm to about 90 µm, about 45 µm to about 85 µm, about 45 µm to about 80 µm, about 45 µm to about 75 µm, about 45 µm to about 70 µm, about 45 µm to about 65 µm, about 45 µm to about 60 µm, about 45 µm to about 55 µm, about 45 µm to about 50 µm, about 50 µm to about 100 µm, about 50 µm to about 95 µm, about 50 µm to about 90 µm, about 50 µm to about 85 µm, about 50 µm to about 80 µm, about 50 µm to about 75 µm, about 50 µm to about 70 µm, about 50 µm to about 65 µm, about 50 µm to about 60 µm, about 50 µm to about 55 µm, about 55 µm to about 100 µm, about 55 µm to about 95 µm, about 55 µm to about 90 µm, about 55 µm to about 85 µm, about 55 µm to about 80 µm, about 55 µm to about 75 µm, about 55 µm to about 70 µm, about 55 µm to about 65 µm, about 55 µm to about 60 µm, about 60 µm to about 100 µm, about 60 µm to about 95 µm, about 60 µm to about 90 µm, about 60 µm to about 85 µm, about 60 µm to about 80 µm, about 60 µm to about 75 µm, about 60 µm to about 70 µm, about 60 µm to about 65 µm, about 65 µm to about 100 µm, about 65 µm to about 95 µm, about 65 µm to about 90 µm, about 65 µm to about 85 µm, about 65 µm to about 80 µm, about 65 µm to about 75 µm, about 65 µm to about 70 µm, about 70 µm to about 100 µm, about 70 µm to about 95 µm, about 70 µm to about 90 µm, about 70 µm to about 85 µm, about 70 µm to about 80 µm, about 70 µm to about 75 µm, about 75 µm to about 100 µm, about 75 µm to about 95 µm, about 75 µm to about 90 µm, about 75 µm to about 85 µm, about 75 µm to about 80 µm, about 80 µm to about 100 µm, about 80 µm to about 95 µm, about 80 µm to about 90 µm, about 80 µm to about 85 µm, about 85 µm to about 100 µm, about 85 µm to about 95 µm, about 85 µm to about 90 µm, about 90 µm to about 100 µm, about 90 µm to about 95 µm, or about 95 µm to about 100 µm. In some embodiments, the D 50 is about 5 µm, about 10 µm, about 15 µm, about 16 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, or about 100 µm. In some embodiments, the D 50 is about 10 µm, about 11 µm, about 12 µm, about 13 µm, about 14 µm, about 15 µm, about 16 µm, about 17 µm, about 18 µm, about 19 µm, or about 20 µm, or a value within a range defined by any of the preceding values. In some embodiments, the Dso value is about 16 µm. The Dso value can be measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, laser diffraction and disc centrifugation.

[0332] In some embodiments, the particles have a particle size distribution (D-value, D 50 ), of 5 µm to 100 µm, such as 5 µm to 95 µm, 5 µm to 90 µm, 5 µm to 85 µm, 5 µm to 80 µm, 5 µm to 75 µm, 5 µm to 70 µm, 5 µm to 65 µm, 5 µm to 60 µm, 5 µm to 55 µm, 5 µm to 50 µm, 5 µm to 45 µm, 5 µm to 40 µm, 5 µm to 35 µm, 5 µm to 30 µm, 5 µm to 25 µm, 5 µm to 20 µm, 5 µm to 15 µm, 5 µm to 10 µm, 10 µm to 100 µm, 10 µm to 95 µm, 10 µm to 90 µm, 10 µm to 85 µm, 10 µm to 80 µm, 10 µm to 75 µm, 10 µm to 70 µm, 10 µm to 65 µm, 10 µm to 60 µm, 10 µm to 55 µm, 10 µm to 50 µm, 10 µm to 45 µm, 10 µm to 40 µm, 10 µm to 35 µm, 10 µm to 30 µm, 10 µm to 25 µm, 10 µm to 20 µm, 10 µm to 15 µm, 15 µm to 100 µm, 15 µm to 95 µm, 15 µm to 90 µm, 15 µm to 85 µm, 15 µm to 80 µm, 15 µm to 75 µm, 15 µm to 70 µm, 15 µm to 65 µm, 15 µm to 60 µm, 15 µm to 55 µm, 15 µm to 50 µm, 15 µm to 45 µm, 15 µm to 40 µm, 15 µm to 35 µm, 15 µm to 30 µm, 15 µm to 25 µm, 15 µm to 20 µm, 20 µm to 100 µm, 20 µm to 95 µm, 20 µm to 90 µm, 20 µm to 85 µm, 20 µm to 80 µm, 20 µm to 75 µm, 20 µm to 70 µm, 20 µm to 65 µm, 20 µm to 60 µm, 20 µm to 55 µm, 20 µm to 50 µm, 20 µm to 45 µm, 20 µm to 40 µm, 20 µm to 35 µm, 20 µm to 30 µm, 20 µm to 25 µm, 25 µm to 100 µm, 25 µm to 95 µm, 25 µm to 90 µm, 25 µm to 85 µm, 25 µm to 80 µm, 25 µm to 75 µm, 25 µm to 70 µm, 25 µm to 65 µm, 25 µm to 60 µm, 25 µm to 55 µm, 25 µm to 50 µm, 25 µm to 45 µm, 25 µm to 40 µm, 25 µm to 35 µm, 25 µm to 30 µm, 30 µm to 100 µm, 30 µm to 95 µm, 30 µm to 90 µm, 30 µm to 85 µm, 30 µm to 80 µm, 30 µm to 75 µm, 30 µm to 70 µm, 30 µm to 65 µm, 30 µm to 60 µm, 30 µm to 55 µm, 30 µm to 50 µm, 30 µm to 45 µm, 30 µm to 40 µm, 30 µm to 35 µm, 35 µm to 100 µm, 35 µm to 95 µm, 35 µm to 90 µm, 35 µm to 85 µm, 35 µm to 80 µm, 35 µm to 75 µm, 35 µm to 70 µm, 35 µm to 65 µm, 35 µm to 60 µm, 35 µm to 55 µm, 35 µm to 50 µm, 35 µm to 45 µm, 35 µm to 40 µm, 40 µm to 100 µm, 40 µm to 95 µm, 40 µm to 90 µm, 40 µm to 85 µm, 40 µm to 80 µm, 40 µm to 75 µm, 40 µm to 70 µm, 40 µm to 65 µm, 40 µm to 60 µm, 40 µm to 55 µm, 40 µm to 50 µm, 40 µm to 45 µm, 45 µm to 100 µm, 45 µm to 95 µm, 45 µm to 90 µm, 45 µm to 85 µm, 45 µm to 80 µm, 45 µm to 75 µm, 45 µm to 70 µm, 45 µm to 65 µm, 45 µm to 60 µm, 45 µm to 55 µm, 45 µm to 50 µm, 50 µm to 100 µm, 50 µm to 95 µm, 50 µm to 90 µm, 50 µm to 85 µm, 50 µm to 80 µm, 50 µm to 75 µm, 50 µm to 70 µm, 50 µm to 65 µm, 50 µm to 60 µm, 50 µm to 55 µm, 55 µm to 100 µm, 55 µm to 95 µm, 55 µm to 90 µm, 55 µm to 85 µm, 55 µm to 80 µm, 55 µm to 75 µm, 55 µm to 70 µm, 55 µm to 65 µm, 55 µm to 60 µm, 60 µm to 100 µm, 60 µm to 95 µm, 60 µm to 90 µm, 60 µm to 85 µm, 60 µm to 80 µm, 60 µm to 75 µm, 60 µm to 70 µm, 60 µm to 65 µm, 65 µm to 100 µm, 65 µm to 95 µm, 65 µm to 90 µm, 65 µm to 85 µm, 65 µm to 80 µm, 65 µm to 75 µm, 65 µm to 70 µm, 70 µm to 100 µm, 70 µm to 95 µm, 70 µm to 90 µm, 70 µm to 85 µm, 70 µm to 80 µm, 70 µm to 75 µm, 75 µm to 100 µm, 75 µm to 95 µm, 75 µm to 90 µm, 75 µm to 85 µm, 75 µm to 80 µm, 80 µm to 100 µm, 80 µm to 95 µm, 80 µm to 90 µm, 80 µm to 85 µm, 85 µm to 100 µm, 85 µm to 95 µm, 85 µm to 90 µm, 90 µm to 100 µm, 90 µm to 95 µm, or 95 µm to 100 µm. In some embodiments, the D 50 is 5 µm, 10 µm, 15 µm, 16 µm, 20 µm, 25 µm, 30 µm, 35 µm, 40 µm, 45 µm, 50 µm, 55 µm, 60 µm, 65 µm, 70 µm, 75 µm, 80 µm, 85 µm, 90 µm, 95 µm, or 100 µm. In some embodiments, the Dso is 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, or 20 µm, or a value within a range defined by any of the preceding values. In some embodiments, the D 50 value is 16 µm. The Dso value can be measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, laser diffraction and disc centrifugation.

[0333] The SDDs of the present disclosure have a low residual solvent content. "Residual solvent content," as used herein, refers to the amount of solvent present in the SDD following spray drying, immediately upon exit from the spray dryer. The presence of solvent in the SDD lowers the glass transition temperature (T g ) of the dispersion. In some embodiments, mobility of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the SDD and its propensity to phase separate and crystallize decreases as the amount of residual solvent in the SDD decreases. In some embodiments, the SDDs have a residual solvent content of not more than about 10 wt%, such as not more than about 5 wt%, or not more than about 1 wt%. For example, the SDDs have a residual solvent content of about 2 wt%, about 1.9 wt%, about 1.8 wt%, about 1.7 wt%, about 1.6 wt%, about 1.5 wt%, about 1.4 wt%, about 1.3 wt%, about 1.2 wt%, about 1.1 wt%, about 1 wt%, about 0.9 wt%, about 0.8 wt%, about 0.7 wt%, about 0.6 wt%, about 0.5 wt%, or less. In some embodiments, the SDDs have a residual solvent content of less than about 2 wt%. In some embodiments, the SDDs have a residual solvent content of less than about 1 wt%. In some embodiments, the SDDs have a residual solvent content of about 0.5 wt% or less. In some embodiments, the SDDs have a residual solvent content of not more than 10 wt%, such as not more than 5 wt%, or not more than 1 wt%. For example, the SDDs may have a residual solvent content of 2 wt%, 1.9 wt%, 1.8 wt%, 1.7 wt%, 1.6 wt%, 1.5 wt%, 1.4 wt%, 1.3 wt%, 1.2 wt%, 1.1 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, or less. In some embodiments, the SDDs have a residual solvent content of less than 2 wt%. In some embodiments, the SDDs have a residual solvent content of less than 1 wt%. In some embodiments, the SDDs have a residual solvent content of 0.5 wt% or less.

[0334] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the spray-dried dispersion is substantially amorphous. As used herein, "substantially amorphous" means that the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in amorphous form is at least 60 wt% and that the amount of crystalline form present does not exceed 20 wt%. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the dispersion is "almost completely amorphous," meaning that at least 90 wt% of the drug is amorphous, or that the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the crystalline form does not exceed 10 wt%. Amounts of crystalline drug can be measured by powder X-ray diffraction (PXRD), scanning electron microscope (SEM) analysis, differential scanning calorimetry (DSC), polarized light microscopy (PLM), or any other standard quantitative or qualitative measurement used to detect crystalline material. Without wishing to be bound by any theory, it is believed that the amorphous, or non-crystalline form, in combination with the polymer, leads to greater ease of dissolution and absorption in the desired location, for example, the intestines, resulting in enhanced bioavailability as compared to a crystalline form of the compound of Formula (I) without polymer.Process for preparing spray-dried dispersions

[0335] Provided in the present disclosure are methods for preparing a spray-dried dispersion containing a polymer and the compound of Formula (I), or a pharmaceutically acceptable salt thereof, such as the SDDs described herein. In some embodiments, the method includes 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 produce the spray-dried dispersion, wherein the spray-drying forms homogeneous particles of the compound of Formula (I) and the polymer. In some embodiments, the product obtained by spray-drying is dried to remove the solvent or solvent mixture. In some embodiments, the organic solvent is acetone.

[0336] The SDDs disclosed herein can be obtained by spray-drying a mixture comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, one or more polymer(s), and an appropriate solvent or solvent mixture. Spray-drying involves atomization of a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. Atomization can be done, for example, through a two-fluid or pressure or electrosonic nozzle, or on a rotating disk.

[0337] Spray-drying converts a liquid feed to a dried particulate form. In some embodiments, spray-drying involves the atomization of a liquid feed solution into a spray of droplets and contacting the droplets with hot air or gas in a drying chamber. The composition to be spray-dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray-drying apparatus. In some embodiments, the composition is a solution that is clear and free of undissolved solids. In some embodiments, the sprays are produced by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. Commercially available types of apparatus can be used to conduct the spray-drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro). Techniques and methods for spray-drying can also be found in Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall, "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0338] In some embodiments, the spray-drying is conducted with an inlet temperature of from about 40°C to about 100°C, for example, from about 60°C to about 80°C, or from about 70°C to about 75°C. In some embodiments, the spray-drying is conducted with an inlet temperature of about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 70°C, about 72°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C, or within a range defined by any of the preceding values. In some embodiments, the inlet temperature is about 60°C to about 80°C. In some embodiments, the spray-drying is conducted with an inlet temperature of about 61°C, about 63°C, about 65°C, about 67°C, about 69°C, about 71°C, about 73°C, about 75°C, about 77°C, about 79°C, about 81°C, about 83°C, or about 85°C, or within a range defined by any of the preceding values. In some embodiments, the inlet temperature is about 72°C.

[0339] In some embodiments, the spray-drying is conducted with an inlet temperature of from 40°C to 100°C, for example, from 60°C to 80°C, or from 70°C to 75°C. In some embodiments, the spray-drying is conducted with an inlet temperature of 40°C, 45°C, 50°C, 55°C, 60°C, 70°C, 72°C, 75°C, 80°C, 85°C, 90°C, 95°C, or 100°C, or within a range defined by any of the preceding values. In some embodiments, the inlet temperature is 60°C to 80°C. In some embodiments, the spray-drying is conducted with an inlet temperature of 61°C, 63°C, 65°C, 67°C, 69°C, 71°C, 73°C, 75°C, 77°C, 79°C, 81°C, 83°C, or 85°C, or within a range defined by any of the preceding values. In some embodiments, the inlet temperature is 72°C.

[0340] In some embodiments, the spray-drying is conducted with an outlet temperature of from about 20°C to about 75°C, for example, from about 25°C to about 50°C, or from about 30°C to about 40°C. In some embodiments, the spray-drying is conducted with an outlet temperature of about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, or about 75°C, or within a range defined by any of the preceding values. In some embodiments, the outlet temperature is about 25°C to about 45°C. In some embodiments, the spray-drying is conducted with an outlet temperature of about 24°C, about 26°C, about 28°C, about 30°C, about 32°C, about 34°C, about 36°C, about 38°C, about 40°C, about 42°C, about 44°C, or about 46°C, or within a range defined by any of the preceding values. In some embodiments, the outlet temperature is about 35°C.

[0341] In some embodiments, the spray-drying is conducted with an outlet temperature of from 20°C to 75°C, for example, from 25°C to 50°C, or from 30°C to 40°C. In some embodiments, the spray-drying is conducted with an outlet temperature of 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or 75°C, or within a range defined by any of the preceding values. In some embodiments, the outlet temperature is 25°C to 45°C. In some embodiments, the spray-drying is conducted with an outlet temperature of 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C, 44°C, or 46°C, or within a range defined by any of the preceding values. In some embodiments, the outlet temperature is 35°C.

[0342] In some embodiments, the method involves removing the organic solvent after formation of the spray-dried dispersion. In some embodiments, the organic solvent is removed by drying the SDD. In some embodiments, a secondary drying process, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, rotary drum drying or biconical vacuum drying is used to remove or reduce residual solvents, such as the organic solvent, to pharmaceutically acceptable levels. In some embodiments, the SDD is dried with a convection tray dryer.

[0343] In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a bulk density of less than about 0.2 g / mL, or less than about 0.15 g / mL. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a bulk density of about 0.19 g / mL, about 0.18 g / mL, about 0.17 g / mL, about 0.16 g / mL, about 0.15 g / mL, about 0.14 g / mL, about 0.13 g / mL, about 0.12 g / mL, about 0.11 g / mL, about 0.1 g / mL, about 0.09 g / mL, about 0.08 g / mL, about 0.07 g / mL, about 0.06 g / mL or about 0.05 g / mL, or within a range defined by any of the preceding values. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a bulk density of less than 0.2 g / mL, or less than 0.15 g / mL. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a bulk density of 0.19 g / mL, 0.18 g / mL, 0.17 g / mL, 0.16 g / mL, 0.15 g / mL, 0.14 g / mL, 0.13 g / mL, 0.12 g / mL, 0.11 g / mL, 0.1 g / mL, 0.09 g / mL, 0.08 g / mL, 0.07 g / mL, 0.06 g / mL or 0.05 g / mL, or within a range defined by any of the preceding values. The term "bulk density," as used herein, refers to a property of powders and is defined as the mass of many particles of the material divided by the total volume they occupy. The total volume includes particle volume, inter-particle void volume and internal pore volume.

[0344] In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a tapped density of less than about 0.3 g / mL, or less than about 0.25 g / mL. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a tapped density of about 0.29 g / mL, about 0.28 g / mL, about 0.27 g / mL, about 0.26 g / mL, about 0.25 g / mL, about 0.24 g / mL, about 0.23 g / mL, about 0.22 g / mL, about 0.21 g / mL, about 0.2 g / mL, or about 0.19 g / mL, or within a range defined by any of the preceding values. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a tapped density of less than 0.3 g / mL, or less than 0.25 g / mL. In some embodiments, the homogeneous particles produced by the methods of the present disclosure have a tapped density of 0.29 g / mL, 0.28 g / mL, 0.27 g / mL, 0.26 g / mL, 0.25 g / mL, 0.24 g / mL, 0.23 g / mL, 0.22 g / mL, 0.21 g / mL, 0.2 g / mL, or 0.19 g / mL, or within a range defined by any of the preceding values. The term "tap density" or "tapped density," as used herein, refers to a measure of the density of a powder. The tapped density of a pharmaceutical powder is determined using a tapped density tester, which is set to tap the powder at a fixed impact force and frequency. Tapped density by the USP method is determined by a linear progression of the number of taps.Deuterated Compounds

[0345] Also disclosed herein are compounds having the structure of the following formula (II): or a pharmaceutically acceptable salt thereof, wherein: each R 1< is independently C(R A< ) 3 ; each R A< is independently hydrogen or deuterium; each R 2< is independently hydrogen or deuterium; each R 3< is independently hydrogen or deuterium; R 4< is R 5< is hydrogen or deuterium; R 6< is C(R A< ) 3 ; and R 7< is C(R B< ) 3 , wherein at least one of R A< , R B< , R 2< , R 3< and R 5< is deuterium.

[0346] With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

[0347] In some embodiments, the compound of Formula (II) may be one of the following, or a pharmaceutically acceptable salt thereof: Pharmaceutical compositions

[0348] The methods and uses disclosed herein can comprise administering the compound of Formula (I) as a pharmaceutical composition.

[0349] In some embodiments of the methods described herein, 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 a pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients.

[0350] Also provided herein is a pharmaceutical composition 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, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0351] In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that does not comprise a spray-dried dispersion of the compound of Formula (I), as specified, e.g., in Example 1. Accordingly, in some embodiments, the pharmaceutical composition does not comprise any of the following polymers: hydroxypropylmethylcellulose acetate succinate-L (HPMCAS-L); polyvinyl pyrrolidone vinyl acetate 64 (PVP / VA 64); HPMCAS-M; and methyl methacrylate copolymer (1:1) (Eudragit ®< L100).

[0352] In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is not the reference formulation described in Example 9. Accordingly, in some embodiments, the pharmaceutical composition does not comprise at least three of the excipients selected from caprylic / capric triglyceride (Labrafac ®< Lipophile, Gattefossé, France); propylene glycol dicrapolate / dicaprate (Labrafac ®< PG, Gattefossé, France); oleoyl polyoxyl-6 glycerides (Labrafil ®< M 1944 CS, Gattefossé, France); polysorbate 20; polyoxyl castor oil (Kolliphor ®< RH 40, BASF, Germany); polyoxyl 15 hydroxystearate (Kolliphor ®< HS 15, BASF, Germany); lauroyl polyoxyl-32 glycerides (Gelucire ®< 44 / 14, Gattefossé, France); d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); and diethylene glycol monoethyl ether (Transcutol ®< , Gattefossé, France).

[0353] In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is the formulation described in Example 9. In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is the formulation described in Example 11. In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is the formulation described in Example 12. In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is the formulation described in Example 13.

[0354] In some embodiments, the pharmaceutical compositions include a spray-dried dispersion containing a polymer and the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the pharmaceutical composition includes the SDD comprising a compound of Formula (I) and one or more pharmaceutically acceptable excipients. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of about 20% to about 90% w / w of the composition, such as about 20% to about 85%, about 20% to about 80%, about 20% to about 75%, about 20% to about 70%, about 20% to about 65%, about 20% to about 60%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 20% to about 25%, about 25% to about 90%, about 25% to about 85%, about 25% to about 80%, about 25% to about 75%, about 25% to about 70%, about 25% to about 65%, about 25% to about 60%, about 25% to about 55%, about 25% to about 50%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 90%, about 30% to about 85%, about 30% to about 80%, about 30% to about 75%, about 30% to about 70%, about 30% to about 65%, about 30% to about 60%, about 30% to about 55%, about 30% to about 50%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 90%, about 35% to about 85%, about 35% to about 80%, about 35% to about 75%, about 35% to about 70%, about 35% to about 65%, about 35% to about 60%, about 35% to about 55%, about 35% to about 50%, about 35% to about 45%, about 35% to about 40%, about 40% to about 90%, about 40% to about 85%, about 40% to about 80%, about 40% to about 75%, about 40% to about 70%, about 40% to about 65%, about 40% to about 60%, about 40% to about 55%, about 40% to about 50%, about 40% to about 45%, about 45% to about 90%, about 45% to about 85%, about 45% to about 80%, about 45% to about 75%, about 45% to about 70%, about 45% to about 65%, about 45% to about 60%, about 45% to about 55%, about 45% to about 50%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 55% to about 90%, about 55% to about 85%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 55% to about 60%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 65% to about 90%, about 65% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 90%, about 80% to about 85%, or about 85% to about 90% w / w of the composition. In some embodiments, the SDD is present in an amount of about 40% to about 90% w / w of the composition. In some embodiments, the SDD is present in an amount of about 40% to about 80% w / w of the composition. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of about 60% to about 80% w / w of the composition. In some embodiments, the SDD is present in an amount of about 80% w / w of the composition. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of about 1% to about 20% w / w of the composition, such as about 13% w / w of the composition.

[0356] In some embodiments, the pharmaceutical composition includes the SDD comprising a compound of Formula (I) and one or more pharmaceutically acceptable excipients. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of 20% to 90% w / w of the composition, such as 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to about 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 90%, 65% to 85%, 65% to 80%, 65% to 75%, 65% to 70%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 90%, 80% to 85%, or about 85% to 90% w / w of the composition. In some embodiments, the SDD is present in an amount of 40% to 90% w / w of the composition. In some embodiments, the SDD is present in an amount of 40% to 80% w / w of the composition. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of 60% to 80% w / w of the composition. In some embodiments, the SDD is present in an amount of 80% w / w of the composition. In some embodiments, the SDD is present in the pharmaceutical composition in an amount of about 1% to about 20% w / w of the composition, such as about 13% w / w of the composition.

[0357] In some embodiments of the pharmaceutical compositions disclosed herein (e.g., a composition including an SDD), the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a lubricant, and combinations thereof. In some embodiments, the pharmaceutical excipients are selected from the group consisting of a glidant, a filler, a disintegrant, a lubricant, and a combination thereof.

[0358] In some embodiments, the pharmaceutical composition includes a filler. In some embodiments, the filler is selected from among binders, diluents, disintegrants, glidants, surfactants, and combinations thereof.

[0359] In some embodiments, the filler include saccharides (e.g., sugars, starch, and cellulose), gelatin, calcium carbonate, and synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene glycol, and poloxamers (e.g., Poloxamer 188, a copolymer of polyoxyethylene and polyoxypropylene)). Exemplary fillers include, but are not limited to, glucose, sucrose, lactose, a starch, including modified starches such as sodium starch glycolate (e.g., Explotab ®< ), xylitol, dextrin, saccharose, sorbitol, mannitol (e.g., Parteck ®< M 200 (mannitol with an average particle size of about 50 µm to about 500 µm) or Parteck ®< M 100 (mannitol with an average particle size of less than 212 µm)), a cellulose, a polyvinylpyrrolidone, a polyethylene glycol, a polyvinyl alcohol, a polymethacrylate, dibasic calcium phosphate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oils, a mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, aliginic acid, alginates (e.g., sodium alginate), calcium silicate, and ion exchange resins. Exemplary cellulose fillers include microcrystalline cellulose (e.g., Avicel ®< PH-101 (microcrystalline cellulose with an average particle size of approximately 50 µm) or Avicel ®< PH 200 (microcrystalline cellulose with an average particle size of approximately 180 µm)), methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose. Exemplary fillers include cross-linked polyvinylpyrrolidone such as with an average particle size of 90 µm to 130 µm) or with an average particle size of 10 µm to 30 µm). Other fillers known to those of skill in the art are also contemplated as being useful when formulated in the pharmaceutical compositions described herein.

[0360] In some embodiments, the filler is a binder. Binders include agents that hold the active pharmaceutical ingredient (e.g., spray-dried dispersion containing a polymer and the compound of Formula (I), or a pharmaceutically acceptable salt thereof) and inactive ingredients together in a cohesive mix. Exemplary binders include, but are not limited to, glucose, sucrose, lactose, a starch, including modified starches such as sodium starch glycolate (Explotab ®< ), xylitol, dextrin, saccharose, sorbitol, mannitol (e.g., Parteck ®< M 200 (mannitol with an average particle size of about 50 µm to about 500 µm), Parteck ®< M 100 (mannitol with an average particle size of less than 212 µm)), gelatin, gum tragacanth, acacia mucilage, a cellulose, a polyvinylpyrrolidone, a polyethylene glycol, a polyvinyl alcohol, a polymethacrylate, and sodium starch glycolate. Exemplary cellulose fillers include microcrystalline cellulose (e.g., Avicel ®< PH-101 (microcrystalline cellulose with an average particle size of approximately 50 µm) or Avicel ®< PH 200 (microcrystalline cellulose with an average particle size of approximately 180 µm)), cellulose ethers, methyl cellulose, ethyl cellulose, croscarmellose sodium, sodium carboxy methyl cellulose starches, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Exemplary polyvinylpyrrolidone fillers include cross-linked polyvinylpyrrolidone such as Kollidon ®< CL (crospovidone with an average particle size of 90 µm to 130 µm) or Kollidon ®< CL-SF (crospovidone with an average particle size of 10 µm to 30 µm). Other binders known to those of skill in the art are also contemplated as being useful when formulated in the compositions described herein.

[0361] In some embodiments, the filler is a diluent. Suitable diluents include, but are not limited to, lactose, mannitol, isomalt, sucrose, dextrose, and sorbitol.

[0362] In some embodiments, the filler is a disintegrant. Disintegrants include any agent that promotes breakup of the formulation in an aqueous environment, for example, to promote more rapid release of the active pharmaceutical ingredient (e.g., the compound of Formula (I), or a pharmaceutically acceptable salt thereof). Exemplary disintegrants include, but are not limited to, starch and modified starches, such as corn starch, potato starch, sodium starch glycolate or croscarmellose sodium, alginic acid, alginates, such as sodium alginate, polyvinylpyrrolidone, bentonite, methylcellulose, agar, carboxymethylcellulose, crospovidone, acid-carbonate effervescent systems, such as citric acid with bicarbonate salts, and ion exchange resins. Other disintegrants known to those of skill in the art are also contemplated as being useful when formulated in the compositions described herein.

[0363] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 w / w% to about 30 w / w% of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 5 w / w% to about 15 w / w% of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 10 w / w% of the disintegrant. In some embodiments, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, and sodium bicarbonate. In some embodiments, the disintegrant is croscarmellose sodium.

[0364] In some embodiments, the filler is a glidant. Glidants can be used to improve the flowability of a powder or granules or both. Glidants include, but are not limited to, silicone dioxide, such as colloidal silicon dioxide or hydrated silicon dioxide, magnesium silicate, magnesium aluminometasilicate, talc, starch, calcium silicate, light anhydrous silicic acid, and silicon dioxide aerogels.

[0365] In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / w% to about 5 w / w% of the glidant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / w% to about 1 w / w% of the glidant. In some embodiments, the pharmaceutical composition comprises about 0.67 w / w% of the glidant. In some embodiments, the glidant is selected from calcium silicate, silicon dioxide, and talc. In some embodiments, the glidant is calcium silicate.

[0366] In some embodiments, the filler is a surfactant, wetting agent, solubilizer, or combination thereof. Examples include, but are not limited to, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., Tween ®< ), polyoxyethylene stearates, sodium dodecylsulfate, tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton). Other examples include, but are not limited to, poloxamers such as Pluronic ®< F68, F127, and F108, which are block copolymers of ethylene oxide and propylene oxide, and polyxamines such as Tetronic ®< 908 (also known as Poloxamine ®< 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol ®< OT, which is a dioctyl ester of sodium sulfosuccinic acid (available from American Cyanimid), Duponol ®< P, which is a sodium lauryl sulfate (available from DuPont), Triton ®< X-200, which is an alkyl aryl polyether sulfonate (available from Rohm and Haas), Tween ®< 20 and Tween ®< 80, which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals), Carbowax ™< 3550 and 934, which are polyethylene glycols (available from Union Carbide), Crodesta ™< F-110, which is a mixture of sucrose stearate and sucrose distearate, and Crodesta ™< SL-40 (both available from Croda Inc.), and SA90HCO, which has the chemical formula C 18 H 37 -CH 2 (CON(CH 3 )CH 2 (CHOH) 4 CH 2 OH) 2 .

[0367] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the pharmaceutical composition comprises about 30 w / w% to about 99 w / w% of the filler. In some embodiments, the pharmaceutical composition comprises about 50 w / w% to about 90 w / w% of the filler. In some embodiments, the pharmaceutical composition comprises about 75.5 w / w% of the filler. In some embodiments, the filler is selected from mannitol, microcrystalline cellulose, lactose, starch, isomalt, silicified microcrystalline cellulose, Dicalcium Phosphate, maltodextrin, and a combination thereof. In some embodiments, the filler is a combination of mannitol and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 30 w / w% to about 80 w / w% of mannitol. In some embodiments, the pharmaceutical composition comprises about 50 w / w% to about 60 w / w% of mannitol. In some embodiments, the pharmaceutical composition comprises about 56 w / w% of mannitol. In some embodiments, the pharmaceutical composition comprises about 1 w / w% to about 50 w / w% of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 10 w / w% to about 30 w / w% of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 20 w / w% of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 56 w / w% of mannitol and about 20 w / w% of microcrystalline cellulose.

[0368] In some embodiments, the pharmaceutical composition includes a lubricant. Lubricants are agents added to pharmaceutical formulations to reduce friction during processing and prevent ingredients from clumping together. Exemplary lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, sodium stearate, zinc stearate, stearic acid, vegetable stearin, adipic acid, waxy fatty acids, such as glyceryl behenate, a hydrogenated vegetable oil, a mineral oil, a polyethylene glycol, lycopodium, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium chloride, sterotex, glycerol monostearate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, and sodium acetate. Other lubricants known to those of skill in the art are also contemplated as being useful when formulated in the compositions described herein.

[0369] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / w% to about 10 w / w% of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / w% to about 1 w / w% of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5 w / w% of the lubricant. In some embodiments, the pharmaceutical lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid sodium lauryl sulfate, sodium oleate, glyceryl behenate, and talc. In some embodiments, the lubricant is sodium stearyl fumarate.

[0370] In some embodiments, the pharmaceutical composition comprises: (a) the spray-dried dispersion comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer; (b) a glidant; (c) a filler; and (d) a disintegrant.

[0371] In some embodiments, the pharmaceutical composition comprises: (a) about 1 w / w% to about 20 w / w% of the spray-dried dispersion comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer; (b) about 0.1 w / w% to about 1 w / w% of a glidant; (c) about 50 w / w% to about 90 w / w% of a filler; and (d) about 5 w / w% to about 0.2 w / w% of a disintegrant.

[0372] In some embodiments, the pharmaceutical composition comprises: (a) about 13 w / w% of the spray-dried dispersion comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer; (b) about 0.67 w / w% of a glidant; (c) about 75.5 w / w% of a filler; and (d) about 10 w / w% of a disintegrant.

[0373] In some embodiments, the pharmaceutical composition comprises: (a) the spray-dried dispersion of Example 3; (b) calcium silicate; (c) a combination of mannitol and microcrystalline cellulose; and (d) croscarmellose sodium.

[0374] In some embodiments, the pharmaceutical composition comprises: (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% of calcium silicate; (c) about 50 w / w% to about 60 w / w% of mannitol and about 10 w / w% to about 30 w / w% of microcrystalline cellulose; and (d) about 5 w / w% to about 0.2 w / w% of croscarmellose sodium.

[0375] In some embodiments, the pharmaceutical composition comprises: (a) about 13 w / w% of the spray-dried dispersion of Example 3; (b) about 0.67 w / w% of calcium silicate; (c) about 56 w / w% of mannitol and about 20 w / w% of microcrystalline cellulose; and (d) about 10 w / w% of croscarmellose sodium.

[0376] Additional excipients can be included in the pharmaceutical formulations of the present disclosure. Further examples of excipients include, but are not limited to, pigments, colorants, flavoring agents, preservatives, and sweeteners. Flavors and colors can be added to improve the taste or appearance of a formulation. Examples of preservatives used in pharmaceutical compositions are aromatic alcohols, such as benzyl or phenol alcohol, antioxidants such as vitamin A, vitamin E, vitamin C, and selenium, amino acids such as cysteine and methionine, citric acid and sodium citrate, or synthetic preservatives such as methyl paraben and propyl paraben. Sweeteners can be added to make the ingredients more palatable, especially in chewable tablets or liquids like syrups.

[0377] Also provided are methods for preparing a pharmaceutical composition, such as a pharmaceutical composition of the present disclosure. In some embodiments, the method includes combining the spray-dried dispersion described herein with one or more pharmaceutically acceptable excipients, e.g., a pharmaceutically acceptable excipient described herein.

[0378] In some embodiments, the method for preparing the pharmaceutical composition comprises: (a) blending the spray-dried dispersion described herein, 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 aggregates and assist with blend uniformity; (d) further blending the intragranular blend of step (c); (e) compaction of the intragranular blend of step (d) via roller compaction to form granules; and (f) milling of ribbon from roller compaction into granules of step (e).

[0379] In some embodiments, the spray-dried dispersion is the spray-dried dispersion described in Example 3.

[0380] The pharmaceutical compositions of the present disclosure are formulated for oral administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. For solid oral preparations such as, for example, powders, capsules, caplets, gelcaps, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0381] Oral pharmaceutical dosage forms can be solid, gel, or liquid. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the solid dosage form is a pill, tablet, capsule, caplet, gelcaps, granules, powder, sachet, melting strip, or melting film. In some embodiments, the solid dosage form is coated. In some embodiments, the coating is an enteric coating, a sugar coating, or a film coating. In some embodiments, the solid dosage form is a coated particle, coated tablet, enterocoated tablet, or enterocoated capsule. In some embodiments, the solid dosage form is a pill or tablet. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated. In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a powder, solution, or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides), or is encapsulated in a capsule (gelatin or cellulose base capsule). Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent form with a combination of other ingredients known to those skilled in the art.

[0382] The pharmaceutical compositions of the present disclosure can contain, per dosage unit, e.g., tablet, capsule, powder, and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.

[0383] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated in unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg to about 200 mg in the unit dosage form. For example, about 5 mg to about 175 mg, about 5 mg to about 150 mg, about 5 mg to about 125 mg, about 5 mg to about 100 mg, about 5 mg to about 75 mg, about 5 mg to about 50 mg, about 5 mg to about 25 mg, about 25 mg to about 200 mg, about 25 mg to about 175 mg, about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 200 mg, about 75 mg to about 175 mg, about 75 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 175 mg, about 100 mg to about 150 mg, about 100 mg to about 125 mg, about 125 mg to about 200 mg, about 125 mg to about 175 mg, about 125 mg to about 150 mg, about 150 mg to about 200 mg, about 150 mg to about 175 mg, or about 175 mg to about 200 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 25 mg to about 125 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 75 mg to about 150 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg, about 10 mg, about 25 mg, about 35 mg, about 50 mg, about 65 mg, about 75 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg in the unit dosage form, or within a range defined by any of the preceding values. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 50 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 100 mg in the unit dosage form.. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of about 25 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 5 mg to 250 mg in the unit dosage form. For example, 5 mg to 175 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 100 mg, 5 mg to 75 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 200 mg, 25 mg to 175 mg, 25 mg to 150 mg, 25 mg to 125 mg, 25 mg to 100 mg, 25 mg to 75 mg, 25 mg to 50 mg, 50 mg to 200 mg, 50 mg to 175 mg, 50 mg to 150 mg, 50 mg to 125 mg, 50 mg to 100 mg, 50 mg to 75 mg, 75 mg to 200 mg, 75 mg to 175 mg, 75 mg to 150 mg, 75 mg to 125 mg, 75 mg to 100 mg, 100 mg to 200 mg, 100 mg to 175 mg, 100 mg to 150 mg, 100 mg to 125 mg, 125 mg to 200 mg, 125 mg to 175 mg, 125 mg to 150 mg, 150 mg to 200 mg, 150 mg to 175 mg, or 175 mg to 200 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 25 mg to 125 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 75 mg to 150 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 5 mg, 10 mg, 25 mg, 35 mg, 50 mg, 65 mg, 75 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg in the unit dosage form, or within a range defined by any of the preceding values. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 50 mg in the unit dosage form. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in an amount of 100 mg in the unit dosage form. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated as a tablet. In some embodiments, the tablet is coated. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated as capsules. In some embodiments, the pharmaceutical compositions are in sachet form. In some embodiments, the pharmaceutical compositions are in granule form.

[0384] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose of about 25 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose 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 administered in a dose of about 75 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose of about 100 mg, based on the weight of the free base.

[0385] In some embodiments, the pharmaceutical composition is administered in 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. In some embodiments, the pharmaceutical composition is administered in 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. In some embodiments, the pharmaceutical composition is administered in 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. In some embodiments, the pharmaceutical composition is administered in a dose of about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0386] In some embodiments, the pharmaceutical composition comprises about 25 mg 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 50 mg 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 75 mg 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 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0387] The daily dosage of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition as described in the present disclosure can be varied over a wide range from about 1.0 mg to about 10,000 mg per adult human per day, or higher, or any range therein. For oral administration, the compositions can be provided in the form of tablets containing, for example, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1.0 mg, about 2.5 mg, about 5.0 mg, about 10.0 mg, about 15.0 mg, about 25.0 mg, about 50.0 mg, about 75.0 mg, about 100 mg, about 150 mg, about 200 mg, about 250 or about 500 milligrams of the compound of Formula (I), or pharmaceutically acceptable salt thereof, for the symptomatic adjustment of the dosage to the subject to be treated. In some embodiments, an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, can be supplied at a dosage level of from about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein, for example, the range can be from about 0.5 mg / kg to about 500 mg / kg, about 1.0 mg / kg to about 250 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50.0 mg / kg of body weight per day, about 0.1 mg / kg to about 15.0 mg / kg of body weight per day, about 0.5 mg / kg to about 7.5 mg / kg of body weight per day, or any amount to range therein. In some embodiments, an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, can be supplied at a dosage level of from 0.1 mg / kg to 1000 mg / kg of body weight per day, or any range therein, for example, the range can be from 0.5 mg / kg to 500 mg / kg, 1.0 mg / kg to 250 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 50.0 mg / kg of body weight per day, 0.1 mg / kg to 15.0 mg / kg of body weight per day, 0.5 mg / kg to 7.5 mg / kg of body weight per day, or any amount to range therein. A pharmaceutical composition as provided herein can be administered on a regimen of 1 to 4 times per day or in a single daily dose.

[0388] In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 25 mg, based on the weight of the free base. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 50 mg, based on the weight of the free base. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 75 mg, based on the weight of the free base. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 100 mg, based on the weight of the free base. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 150 mg, based on the weight of the free base. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 200 mg, based on the weight of the free base.

[0389] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily in a dose of about 25 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily in a dose 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 administered twice daily in a dose of about 75 mg, based on the weight of the free base. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily in a dose of about 100 mg, based on the weight of the free base.

[0390] In some embodiments, the daily dose of the pharmaceutical composition is about 25 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the daily dose of the pharmaceutical composition is about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the daily dose of the pharmaceutical composition is about 75 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the daily dose of the pharmaceutical composition is about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the daily dose of the pharmaceutical composition is about 150 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the daily dose of the pharmaceutical composition is about 200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0391] In some embodiments, the pharmaceutical composition is administered twice daily in 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. In some embodiments, the pharmaceutical composition is administered twice daily in 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. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily in 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. In some embodiments, the pharmaceutical composition is administered twice daily in a dose of about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0392] In some embodiments, 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, based on the weight of the free base. In some embodiments, 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, based on the weight of the free base. In some embodiments, 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, based on the weight of the free base. In some embodiments, 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, based on the weight of the free base. In some embodiments, 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, based on the weight of the free base. In some embodiments, 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, based on the weight of the free base.

[0393] In some embodiments, the method comprises administering the pharmaceutical composition twice daily in 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. In some embodiments, the method comprises administering the pharmaceutical composition twice daily in 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. In some embodiments, the method comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, twice daily in 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. In some embodiments, the method comprises administering the pharmaceutical composition twice daily in a dose of about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0394] Factors associated with the particular subject being treated, including subject age, weight, diet, and time of administration, can result in the need to adjust dosages. In some embodiments, the subject is a human adult. In some embodiments, the subject is a pediatric subject.

[0395] One skilled in the art will recognize that both in vivo and in vitro trials using suitable, known, and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy subjects and / or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts. For example, determining proper dosages for pediatric subjects can be determined using known methods, including weight, age, and models such as Simcyp ®< Pediatric Simulation modeling (CERTARA, Princeton, N.J.) which can be used to establish a pharmacokinetic approach for dosing that takes into account subject age, ontogeny of the clearance pathways that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and body surface area (BSA).

[0396] In some embodiments, the pharmaceutical compositions of the present disclosure are stable for at least 3 months. In some embodiments, the pharmaceutical compositions are stable for at least 6 months. In some embodiments, the pharmaceutical compositions are stable for at least 9 months. In some embodiments, the pharmaceutical compositions are stable for at least 12 months. For example, the compositions do not exhibit a change (e.g., greater than 5%) in appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over time, e.g., at least 3 months, 6 months, 9 months, or at least 12 months as compared to the original composition after manufacturing. In some embodiments, the pharmaceutical compositions do not exhibit a significant change, as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in one or more of appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over time, e.g., at least 12 months as compared to the original pharmaceutical composition after manufacturing.Kits

[0397] Also provided are kits. Typically, a kit includes one or more pharmaceutical compositions as described herein, e.g., a pharmaceutical composition containing, e.g., a spray-dried dispersion as described in Examples 1-4, or the formulation described in Example 9. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering the pharmaceutical composition as provided herein, and directions for use of the kit (e.g., instructions for treating a subject). In some embodiments, the kit can include a pharmaceutical composition as described herein and a label that indicates that the contents are to be administered to a subject with congenital adrenal hyperplasia. The actual dose of the compound of Formula (I), or pharmaceutically acceptable salt thereof, provided herein depends on the specific formulation, the weight of the patient, and on the condition to be treated.EXAMPLESExample 1: Spray-dried dispersion formulations containing the compound of Formula (I) and various polymers Spray-dried dispersion formulations

[0398] A series of spray-dried dispersion (SDD) formulations containing the compound of Formula (I) and a polymer were prepared. The SDD formulations included: (1) 10% compound of Formula (I) / 90% hydroxypropylmethylcellulose acetate succinate-L (HPMCAS-L); (2) 25% compound of Formula (I) / 75% HPMCAS-L; (3) 40% compound of Formula (I) / 60% HPMCAS-L; (4) 25% compound of Formula (I) / 75% polyvinyl pyrrolidone vinyl acetate 64 (PVP / VA 64); (5) 25% compound of Formula (I) / 60% Cabosil (fumed silica) / 15% HPMCAS-L; (6) 25% compound of Formula (I) / 75% HPMCAS-M; and (7) 25% compound of Formula (I) / 75% methyl methacrylate copolymer (1:1) (Eudragit ®< L100).

[0399] The PVP / VA polymer was a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate with a ratio of 60:40 by weight 1-vinyl-2-pyrrolidone:vinyl acetate with an average molecular weight of 45,000-70,000 (copovidone, sold as Kollidon ®< VA 64, BASF, Florham Park, NJ). The HPMCAS was a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose that was either grade L (HPMCAS-L), with an acetyl content of 5-9%, a succinoyl content of 14-18%, a methoxyl content of 20-24%, and a hydroxypropoxy content of 5-9% (sold by Shin-Etsu, Japan); or grade M (HPMCAS-M), with an acetyl content of 7-11%, a succinoyl content of 10-14%, a methoxyl content of 21-25%, and a hydroxypropoxy content of 5-9% (sold by Shin-Etsu, Japan).Dissolution performance

[0400] Dissolution performance of several of the SDD formulations described above was tested (see FIG. 1). 1000 µgA / mL of each SDD was tested in 0.5 wt% simulated intestinal fluid (SIF) in PBS, pH 6.5. Samples were tested at 5, 10, 20, 45, 90, and 1200 minutes. A lipid formulation containing 10% of the compound of Formula (I) was used as a control. The results are shown in Table 4, below. Table 4. Dissolution data of various SDDs Sample C max90 (µg / mL) AUC 90 (min*µg / mL) C mix90 (µg / mL) Ultra 90 (µg / mL) C 1200 (µg / mL) Ultra 1200 (µg / mL) 276266,080743210671166432227,330306109*268199671862,240708202632217774260,600742113*674194Control80269,580800253799270*Large variability between replicates, high value discarded Non-sink dissolution

[0401] A membrane flux assay was performed (see, e.g., Stewart et al., Mol. Pharm. (2017) 14:2032-2046) and non-sink dissolution data was collected for several of the SDD formulations described above and compared to the compound of Formula (I) and several reference formulations, including a semi-solid lipidic formulation (Reference Formulation 1) and two self-emulsifying drug delivery system (SEDDS) formulations (Reference Formulations 2 and 3). The components of the Reference Formulations are shown in Table 5, below, and include, in addition to the compound of Formula (I), caprylic / capric triglyceride (Labrafac ®< Lipophile, Gattefossé, France); propylene glycol dicrapolate / dicaprate (Labrafac ®< PG, Gattefossé, France); oleoyl polyoxyl-6 glycerides (Labrafil ®< M 1944 CS, Gattefossé, France); polysorbate 20; polyoxyl castor oil (Kolliphor ®< RH 40, BASF, Germany); polyoxyl 15 hydroxystearate (Kolliphor ®< HS 15, BASF, Germany); lauroyl polyoxyl-32 glycerides (Gelucire ®< 44 / 14, Gattefossé, France); d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); and diethylene glycol monoethyl ether (Transcutol ®< , Gattefossé, France). Table 5. Reference formulations (capsules) Formulation (mg / caps) Ref. Formulation 1 Ref. Formulation 2 Ref. Formulation 3Formula (I) 50.050.050.0Labrafac ®< Lipophile 196.0100.0100.0Labrafac ®< PG 102.0--Labrafil ®< M 1944 CS -135.046.0Polysorbate 20 --89.9Kolliphor ®< RH 40 --100.0Kolliphor ®< HS 15 -165.0-Gelucire ®< 44 / 14 95.0--TPGS 57.0-65.0Transcutol ®< -50.050.0Total 500.0500.0500.0

[0402] The assay measured the flux across simulated gastric and intestinal walls via UV spectroscopy (µDiss ProfilerTM, Pion Inc., Billerica, MA). Briefly, the assay was performed as follows. A vertical membrane flux cell consisting of a donor compartment and a receiver compartment, and separated by an Accurel PP 1E (55% porous, 100 µm thickness) polypropylene membrane (3M, Maplewood, MN) (FIG. 2), was impregnated with 50 µL of Pion GIT-0 lipid solution consisting of 20% w / w phospholipid dissolved into dodecane (Pion Inc., Billerica, MA) and attached to the receiver vessel. Both the donor and receiver compartments were agitated by magnetic stirring. The receiver compartment contained a plastic spacer and grating to elevate the stir bar above the membrane. Samples were introduced to the donor vessel by pre-weighing directly into the donor vessel and subsequently adding dissolution medium. Once the dissolution medium was added to the donor vessel, the receiver vessel was inserted into the donor vessel and suspended vertically 5 mm above the donor compartment by a plastic sleeve. For this assay, the simulated gastric (feed) media was 0.1 N HCl, pH 2 and included 200 µgA / mL of each SDD, and the simulated intestinal (receiver) media was 0.5 wt% SIF in PBS, pH 6.5 and included 100 µgA / mL of each SDD. The temperature for the assay was maintained at 44.5°C. UV probes (10 mm path length) connected to a Rainbow UV spectrometer (Pion Inc.) system were used to determine the apparent drug concentration in the receiver vessels. Samples of the donor compartment were removed with a disposable pipet for centrifugation followed by HPLC and DLS analysis of the supernatant. The results are shown in FIG. 3 and Table 6, below. Table 6. Non-sink dissolution data Sample C maxGB (µg / mL) C max90 IB (µg / mL) AUC 4-90IB (min*µg / mL) C 90 (µg / mL) Ultra 90 (µg / mL) C 1200 (µg / ML) Formula (I) 01100031 6806,8008079902 17746,2407373864 6420045365 23553,1805554836 35716,070717783Ref. Formulation 1 2051099,050109--Ref. Formulation 2 24912010,160120--Ref. Formulation 3 2181079,100107--

[0403] The membrane flux of 1 mg / mL gastric barrier / intestinal barrier (GB / IB) 0.5 wt% SIF doses of the compound of Formula (I) and spray-dried dispersions (2) 25% compound of Formula (I) / 75% HPMCAS-L and (4) 25% compound of Formula (I) / 75% PVP / VA 64 were also determined. The results are shown in FIG. 4 as receiver concentration vs. time and flux vs. time (smoothed derivative of receiver concentration x volume / surface area).Example 2: Characterization of a spray-dried dispersion containing 25% of the compound of Formula (I) and 75% of a polyvinyl pyrrolidone vinyl acetate (PVP / VA) polymer SDD stability screening

[0404] Several of the SDDs described in Example 1 were tested for chemical and physical stability. Wet SDD stability studies were performed, with samples stored at both 5°C and 25°C. Measurements were taken after 1 week and 2 weeks of storage. The results are shown in Table 7 below. The column with a retention time of 32.36 min correlates with the compound of Formula (I). Table 7. Wet SDD stability data Retention time (min) 11.0416.7917.2630.9432.26Relative retention time 0.340.520.530.961.00Storage temp Timepoint Total impurities Potency (mgA / g) Std Dev Ref. Std. 0.3799.630.37Formula (I) 0.2699.740.26Sample 1initial0.130.160.2599.460.541001.35°C1 week0.030.030.2699.690.31990.02 weeks0.120.160.2899.450.55990.525°C1 week0.030.040.2699.670.33990.32 weeks0.210.270.2899.240.76980.8Sample 2 initial<LOQ0.070.080.2699.590.412470.35°C1 week<LOQ0.020.030.2699.700.302481.32 weeks<LOQ0.220.270.2799.240.762460.325°C1 week<LOQ0.020.030.2699.690.312480.92 weeks<LOQ0.230.280.2699.230.772461.4LOQ = limit of quantification

[0405] Solution stability studies were also performed, with samples stored at both 5°C and 25°C. Measurements were taken after 1 week and 2 weeks of storage. The results are shown in Table 8 below. The column with a retention time of 32.36 min correlates with the compound of Formula (I). Table 8. SDD solution stability data Retention time (min) 31.5132.26Relative retention time 0.971.00Storage temp Timepoint Total impurities Ref. Std. 0.7499.260.74Formula (I) 0.2699.740.26Sample 1 initial0.3399.670.335°C2 weeks0.2999.710.2925°C2 weeks0.3899.620.38Sample 2 initial0.2599.750.255°C2 weeks0.2699.740.2625°C2 weeks0.3399.670.33

[0406] Stability studies were also performed for the SDD containing 25% of the compound of Formula (I) and 75% PVP / VA 64, with samples stored at both 5°C (closed with desiccant), 25°C (60% RH, closed with desiccant), and 30°C (65% RH, closed with desiccant). Measurements were taken after storage for 1 month, 2 months, 3 months, 6 months, and 12 months. No change in purity was observed after 12 months of storage. The results are shown in Table 9 below. The column with a retention time of 30.2 min correlates with the compound of Formula (I). Table 9. SDD stability data Retention time (min) 28.730.2Relative retention time 0.951.00Storage conditions Timepoint Total impurities Potency (mgA / g) Crystalline Formula (I) 0.2699.740.261001Sample 4 (25% Formula (I):75% PVP / VA 64) initial0.2699.740.262455°C (closed w / desiccant)1 month0.2599.750.252472 months0.2599.750.252443 months0.2699.740.262466 months0.2599.750.2524512 months0.2599.750.2524825°C / 60% RH (closed with desiccant)1 month0.2599.750.252452 months0.2599.750.252473 months0.2599.750.252466 months0.2599.750.2524212 months0.2599.750.2524530°C / 65% RH (closed with desiccant)1 month0.2599.750.252492 months0.2599.750.252423 months0.2599.750.252466 months0.2599.730.2524312 months0.2599.750.25242

[0407] While Samples 1 and 2 showed degradation after about 2 weeks of storage, the SDD containing 25% of the compound of Formula (I) and 75% PVP / VA 64 (Sample 4) was found to be both chemically and physically stable and was further screened and characterized as described below.25% Formula (I) / 75% PVP / VA 64 SDD process parameter screening manufacture Round 1

[0408] The 25% Formula (I) / 75% PVP / VA 64 SDD was prepared on a Pharmaceutical Spray Dryer with 100 kg / hr drying gas capacity (PSD-1). The manufacturing summary is shown in Table 10, below. Table 10. Manufacturing summary of process parameters Formulation 25% Formula (I):75% PVP / VA 64Solids Loading (wt%) 10Batch Size (kg) 1.5Solvent AcetoneAtomizer (Pressure Swirl) SK 80-16Solution Flow-rate (g / min) 160Atomization Pressure (psig) 480Inlet Temperature (°C) 94Outlet Temperature (°C) 40Calculated Outlet Acetone Saturation (% RS) 6.2Dry Yield (%) 73

[0409] Based on the 73% yield observed in the first round of process screening, three sprays were performed to investigate the effect of reducing solution throughput and outlet temperature on product yield. All sprays were conducted at a reduced flow-rate of 110 g / min. The outlet temperature was varied at 40°C (Lot A), 35°C (Lot B), and 30°C (Lot C). The outlet temperature was decreased while maintaining a low outlet acetone saturation to increase the difference between the chamber outlet temperature and the wet SDD T g , thus improving product yields. The spray dryer chamber and outlet ductwork were cleaned between all manufactures. A manufacturing summary is shown in Table 11. Table 11. Manufacturing summary for process parameters (1.5 kg batch size) Description Low Flow-Rate Low Flow-Rate / Low Outlet Temperature Low Flow-Rate / Lower Outlet Temperature Lot ABCSolids Loading (wt%) 101010Batch Size (kg) 1.51.51.5Solvent AcetoneAcetoneAcetoneAtomizer (Pressure Swirl) Steinen A75Steinen A75Steinen A75Solution Flow-Rate (g / min) 110110110Atomization Pressure (psig) 275285285Inlet Temperature (°C) 797263Outlet Temperature (°C) 403530Calculated Outlet Acetone Saturation (% RS) 4.35.26.4Calculated wet SDD T g (°C) 727169Dry Yield (%) 558043

[0410] The conditions used for Lot B were found to give the highest yield. One additional spray was then performed at the same processing conditions as Lot B while increasing the batch size from 1.5 kg to 3.5 kg to evaluate process consistency and to determine if product yield would continue to improve over time. The averaged process conditions for this lot are shown in Table 12. Table 12. Manufacturing summary of process parameters (1.5 kg and 3.5 kg batch sizes) Description Low Flow-Rate / Low Outlet Temperature Low Flow-Rate / Low Outlet Temperature / Larger Batch Size Lot BDSolids Loading (wt%) 1010Batch Size (kg) 1.53.5Solvent AcetoneAcetoneAtomizer (Pressure Swirl) Steinen A75Steinen A75Solution Flow-Rate (g / min) 110110Atomization Pressure (psig) 285285Inlet Temperature (°C) 7272Outlet Temperature (°C) 3535Calculated Outlet Acetone Saturation (% RS) 5.25.2Calculated wet SDD T g (°C) 7171Dry Yield (%) 8084

[0411] The 1.5 kg batch size (Lot D) was sprayed with an 84% yield compared to the 80% yield of the 3.5 kg batch (Lot B).25% Formula (I) / 75% PVP / VA 64 SDD process parameter screening characterisation

[0412] The 25% Formula (I) / 75% PVP / VA 64 SDDs manufactured to evaluate processing parameters were characterized for powder properties, performance, and physical and chemical properties. Testing included particle size distribution by Malvern, determination of bulk and tapped density, microcentrifuge dissolution, modulated differential scanning calorimetry (mDSC), powder x-ray diffraction (PXRD), scanning electron microscope (SEM), and assay and related substances. The results did not show any significant differences between the lots.

[0413] The particle size distribution (PSD) and tabulated powder properties data of the 25% Formula (I) / 75% PVP / VA 64 SDDs are shown in Table 13. All 25% Formula (I) / 75% PVP / VA 64 SDDs were observed to have a very similar PSD with a D 50 of approximately 16 µm. All 25% Formula (I) / 75% PVP / VA 64 SDDs were observed to have low bulk and tapped densities. Table 13. Powder properties of process parameter screening PVP / VA-64 SDDs Sample Lot D 10 (µm) D 50 (µm) D 90 (µm) D (3,2) (µm) D (4,3) (µm) Span Bulk density (g / mL) Tapped density (g / mL) 40°C Outlet A 5 15 34 8 17 1.93 0.12 0.25 35°C Outlet B 5 16 36 9 19 1.97 0.11 0.23 30°C Outlet C 5 15 32 7 17 1.86 0.12 0.27 35°C Outlet, 3.5 kg batch D 5 16 38 9 19 1.98 0.12 0.24

[0414] The 3.5 kg batch size lot was analyzed and compared to process parameter Lot A. Dissolution performance was similar for each of these lots. Dissolution was rapid to C max and high free drug was sustained through 90 minutes. These data are shown in Table 14. Table 14. Dissolution performance of Lot A (1.5 kg batch size) vs. Lot D (3.5 kg batch size) Sample C max90 (µg / mL) AUC 90 (min*µg / mL) C 90 (µg / mL) Ultra 90 (µg / mL) Lot A 44737,740437319Lot D 43737,120433301

[0415] The 25% Formula (I) / 75% PVP / VA 64 SDDs were also evaluated by DSC, PXRD, and SEM. The DSC thermograms showed a single T g at 84°C, indicating homogeneous dispersions. PXRD diffractograms showed no evidence of crystals in the SDDs. SEM images showed inflated sphere morphology with some broken particles and some very small particles.

[0416] Additional testing on Lot B was carried out, which included assessing the chemical / physical stability of both spray solution and SDD prior to secondary drying (wet SDD) to establish maximum in-process hold times. Residual acetone concentration as a function of secondary drying time in a convection tray dryer was also evaluated to nominate tray drying conditions to ensure the SDD is dried below International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for acetone.

[0417] Residual acetone content as a function of drying time was assessed by drying wet SDD in a tray dryer and collecting samples over a 24-hour period. Wet SDD was dried at 40°C / 15% relative humidity (RH) and was observed to dry below ICH acetone guidelines (0.5 wt%, 5000 ppm) by four hours.

[0418] Spray solution hold time was determined by making up a representative solution that contained 2.5 wt% compound of Formula (I), 7.5 wt% PVP / VA 64, and 90 wt% acetone. These solutions were analyzed initially for related substances. and then aged at 5°C and 25°C. Aliquots were taken and analyzed for related substances periodically for 14 days. Results showed no change in impurity profile at either condition through 14 days.

[0419] Wet SDD was analyzed for impurities after storage at 5°C and 25°C for 1 and 2 weeks and compared to the impurity profiles of the ingoing compound of Formula (I) and the SDD that was secondarily dried immediately after spray drying. The impurity profiles were similar to that of the initial dried sample and the ingoing compound of Formula (I) through 2 weeks of storage.

[0420] The wet SDD stability samples were characterized for physical stability by DSC, PXRD, and SEM. DSC thermograms showed a single T g at 81°C, indicative of a homogeneous dispersion with no phase separation. The PXRD diffractograms did not show any evidence of crystals after storage at either condition. SEM images showed a typical morphology of mostly inflated spheres with some broken particles.Example 3: Preparation of a 1000 g batch of a spray-dried dispersion containing 25% of the compound of Formula (I) and 75% PVP / VA 64

[0421] A 1000 g batch of the spray-dried dispersion containing 25% of the compound of Formula (I) and 75% PVP / VA 64 was prepared as described in Example 2 for the 1.5 kg and 3.5 kg batches. Briefly, acetone (90% (w / w) of the total mixture) was added to the mixing tank followed by the addition of 250.0 g of the compound of Formula (I) (2.5% (w / w) of the total mixture). The mixture was mixed for 30 minutes in the dark at a temperature range of 15°C to 27°C. At the end of the mixing period, the solution was clear and free of undissolved solids. The PVP / VA 64 (750.0 g, 7.5% (w / w) of the total mixture) was then added and the mixture was stirred for an additional 30 minutes in the dark at a temperature range of 15°C to 27°C. At the end of the mixing period, the solution was clear and free of undissolved solids.

[0422] The solution was pumped and atomized in a drying chamber. The spray-dried dispersions were prepared in a Pharmaceutical Spray Dryer with 100 kg / hr drying gas capacity (PSD-1). The inlet temperature was set at 75°C (varied between 60°C-90°C). The outlet temperature was set at 35°C (varied between 32°C-38°C). The feed pressure was set at 280 psig (varied between 230-330 psig). The feed rate was set at 110 g / min (varied between 90-130 g / min). The spray dried powder was then dried in a convection tray dryer with a bed depth of ≤ 2.5 cm at 40°C (±5°C) and 15% relative humidity (±10%) for 24 hours under amber light. The residual acetone after drying was < 0.5 wt% (5000 ppm). FIG. 5 is a flow diagram of the manufacturing process.Example 4: Preparation of spray-dried dispersion formulations of the compound of Formula (I) for clinical use

[0423] T...

Claims

1. A pharmaceutical composition in oral solution dosage form comprising: (a) a compound of Formula (I): or a pharmaceutically acceptable salt thereof; (b) one or more of a sweetener, an anti-oxidant, and a flavor; and (c) a liquid vehicle, wherein the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol.

2. The pharmaceutical composition of claim 1, 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.

3. The pharmaceutical composition of claim 1, 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.

4. The pharmaceutical composition of claim 1, 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.

5. The pharmaceutical composition of any one of claims 1-4, comprising a sweetener.

6. The pharmaceutical composition of any one of claims 1-5, comprising about 0.01 w / v% to about 1.5 w / v% of the sweetener.

7. The pharmaceutical composition of any one of claims 1-5, comprising about 0.1 w / v% to about 0.5 w / v% of the sweetener.

8. The pharmaceutical composition of any one of claims 1-5, comprising about 0.15 w / v% of the sweetener.

9. The pharmaceutical composition of any one of claims 1-8, wherein the sweetener is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame.

10. The pharmaceutical composition of any one of claims 1-9, wherein the sweetener is saccharin.

11. The pharmaceutical composition of any one of claims 1-10, comprising an anti-oxidant.

12. The pharmaceutical composition of any one of claims 1-11, comprising about 0.01 w / v% to about 1.5 w / v% of the anti-oxidant.

13. The pharmaceutical composition of any one of claims 1-11, comprising about 0.1 w / v% to about 0.5 w / v% of the anti-oxidant.

14. The pharmaceutical composition of any one of claims 1-11, comprising about 0.17 w / v% of the anti-oxidant.

15. The pharmaceutical composition of any one of claims 1-14, wherein the anti-oxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone, and citric acid.

16. The pharmaceutical composition of any one of claims 1-15, wherein the anti-oxidant is butylated hydroxytoluene.

17. The pharmaceutical composition of any one of claims 1-16, comprising a flavor.

18. The pharmaceutical composition of any one of claims 1-17, comprising about 0.01 w / v% to about 0.5 w / v% of the flavor.

19. The pharmaceutical composition of any one of claims 1-17, comprising about 0.05 w / v% to about 0.2 w / v% of the flavor.

20. The pharmaceutical composition of any one of claims 1-17, comprising about 0.10 w / v% of the flavor.

21. The pharmaceutical composition of any one of claims 1-20, 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.

22. The pharmaceutical composition of any one of claims 1-21, wherein the flavor is FONA orange flavor.

23. The pharmaceutical composition of any one of claims 1-22, comprising about 50 w / v% to about 99.9 w / v% of the liquid vehicle.

24. The pharmaceutical composition of any one of claims 1-22, comprising about 90 w / v% to about 99 w / v% of the liquid vehicle.

25. The pharmaceutical composition of any one of claims 1-22, comprising about 92 w / v% to about 97 w / v% of the liquid vehicle.

26. The pharmaceutical composition of any one of claims 1-22, comprising about 94.6 w / v% of the liquid vehicle.

27. The pharmaceutical composition of any one of claims 1-22, comprising about 70 w / v% to about 80 w / v% of the liquid vehicle.

28. The pharmaceutical composition of any one of claims 1-22, comprising about 75 w / v% of the liquid vehicle.

29. The pharmaceutical composition of any one of claims 1-28, wherein the liquid vehicle is medium-chain triglycerides.

30. The pharmaceutical composition of claim 29, wherein the medium-chain triglycerides is Labrafac Lipophile WL1349.

31. The pharmaceutical composition of any one of claims 1-30, further comprising a surfactant.

32. The pharmaceutical composition of claim 31, comprising about 1 w / v% to about 50 w / v% of the surfactant.

33. The pharmaceutical composition of claim 31, comprising about 10 w / v% to about 30 w / v% of the surfactant.

34. The pharmaceutical composition of claim 31, comprising about 20 w / v% of the surfactant.

35. The pharmaceutical composition of any one of claims 31-34, wherein the surfactant is selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glycerides, sodium lauryl sulfate, Poloxamer, corn oil PEG-6 esters, and hydrogenated palm / palm kernel oil PEG-6 esters.

36. The pharmaceutical composition of any one of claims 31-35, wherein the surfactant is oleoyl polyoxyl-6 glycerides.

37. The pharmaceutical composition of any one of claims 35-36, wherein the oleoyl polyoxyl-6 glycerides is LABRAFIL M 1944 CS.

38. The pharmaceutical composition of any one of claims 1-37, wherein the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol.

39. The pharmaceutical composition of any one of claims 1-38, wherein the liquid vehicle is medium-chain triglycerides.

40. The pharmaceutical composition of any one of claims 1-38, wherein the medium-chain triglycerides is Labrafac Lipophile WL1349.

41. The pharmaceutical composition of claim 1, comprising: (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) a sweetener; (c) an anti-oxidant; (d) a flavor; and (e) a liquid vehicle.

42. The pharmaceutical composition of claim 41, further comprising a surfactant.

43. The pharmaceutical composition of claim 1, comprising: (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% of an anti-oxidant; (d) about 0.05 w / v% to about 0.2 w / v% of a flavor; and (e) about 92 w / v% to about 97 w / v% of a liquid vehicle.

44. The pharmaceutical composition of claim 1, comprising: (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% of a sweetener; (c) about 0.17 w / v% of an anti-oxidant; (d) about 0.1 w / v% of a flavor; and (e) about 94.6 w / v% of a liquid vehicle.

45. The pharmaceutical composition of claim 1, comprising: (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% of an anti-oxidant; (d) about 0.05 w / v% to about 0.2 w / v% of a flavor; (e) about 15 w / v% to about 25 w / v% of a surfactant; and (f) about 70 w / v% to about 80 w / v% of a liquid vehicle.

46. The pharmaceutical composition of claim 1, comprising: (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% of a sweetener; (c) about 0.17 w / v% of an anti-oxidant; (d) about 0.1 w / v% of a flavor; (e) about 20 w / v% of a surfactant; and (f) about 75 w / v% of a liquid vehicle.

47. The pharmaceutical composition of claim 1, comprising: (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 flavor; and (e) medium-chain triglycerides.

48. The pharmaceutical composition of claim 47, further comprising oleoyl polyoxyl-6 glycerides.

49. The pharmaceutical composition of claim 48, comprising: (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 saccharin; (c) about 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene; (d) about 0.05 w / v% to about 0.2 w / v% of FONA orange flavor; and (e) about 92 w / v% to about 97 w / v% of medium-chain triglycerides.

50. The pharmaceutical composition of claim 1, comprising: (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% of saccharin; (c) about 0.17 w / v% of butylated hydroxytoluene; (d) about 0.1 w / v% of FONA orange flavor; and (e) about 94.6 w / v% of medium-chain triglycerides.

51. The pharmaceutical composition of claim 1, comprising: (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 saccharin; (c) about 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene; (d) about 0.05 w / v% to about 0.2 w / v% of FONA orange flavor; (e) about 15 w / v% to about 25 w / v% of oleoyl polyoxyl-6 glycerides; and (f) about 70 w / v% to about 80 w / v% of medium-chain triglycerides.

52. The pharmaceutical composition of claim 1, comprising: (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% of saccharin; (c) about 0.17 w / v% of butylated hydroxytoluene; (d) about 0.1 w / v% of FONA orange flavor; (e) about 20 w / v% of oleoyl polyoxyl-6 glycerides; and (f) about 75 w / v% of medium-chain triglycerides.

53. The pharmaceutical composition of claim 51 or 52, wherein: the oleoyl polyoxyl-6 glycerides is LABRAFIL M 1944 CS; and the medium-chain triglycerides is Labrafac TM Lipophile WL1349.

54. The pharmaceutical composition of any one of claims 1-53, comprising the compound of Formula (I) as a free base.

55. The pharmaceutical composition of any one of claims 1-54, 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 / mL to about 200 mg / mL, based on the weight of the free base.

56. The pharmaceutical composition of claim 55, 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, based on the weight of the free base.

57. The pharmaceutical composition of claim 55, 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.

58. The pharmaceutical composition of claim 55, 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.

59. The pharmaceutical composition of any one of claims 1-58, having a viscosity between about 1 to about 50 centipoise at about 25 °C.

60. A method for preparing the pharmaceutical composition of any one of claims 1-59, comprising: (a) mixing a liquid vehicle with a sweetener; (b) mixing the mixture of step (a) with an anti-oxidant and a flavor; (c) mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof, with the mixture of step (b); and (d) mixing the mixture of step (c) with an additional portion of the liquid vehicle.

61. The method of claim 60, wherein step (a) comprises mixing a liquid vehicle with a sweetener and a surfactant.

62. A pharmaceutical composition of any one of claims 1-59 for use in a method of treating congenital adrenal hyperplasia (CAH) in a subject.

63. The pharmaceutical composition for use according to claim 62, wherein the subject is in a fed state.

64. The pharmaceutical composition for use according to claim 62 or 63, wherein the subject is administered the pharmaceutical composition with a nutritional composition.

65. The pharmaceutical composition for use according to claim 64, wherein the nutritional composition is a liquid dietary supplement comprising about 1000 to about 2000 calories per liter with a fat content greater than about 30%.

66. The pharmaceutical composition for use according to claim 64, wherein the nutritional composition is a liquid dietary supplement comprising 1500 calories per liter with a caloric distribution of 14.7% protein, 32% fat and 53.3% carbohydrate.

67. The pharmaceutical composition for use according to any one of claims 64-66, wherein the nutritional composition is administered in an amount of about 6 to about 12 fluid ounces.

68. The pharmaceutical composition for use according to any one of claims 64-67, wherein the nutritional composition is administered in an amount of about 8 fluid ounces.

69. The pharmaceutical composition for use according to any one of claims 64-68, wherein the nutritional composition is administered within 30 minutes of administration of the pharmaceutical composition.

70. The pharmaceutical composition for use according to any one of claims 63-69, wherein administering the pharmaceutical composition exhibits a positive food effect.

71. The pharmaceutical composition for use according to claim 70, wherein the positive food effect is measured in terms of Cmax, AUC, or a combination thereof of a compound of Formula (I) when comparing oral administration of the pharmaceutical composition in the fed and fasting states.

72. The pharmaceutical composition for use according to any one of claims 63-71, wherein 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.

73. The pharmaceutical composition for use according to any one of claims 63-71, wherein the ratio of the Cmax of the compound of Formula (I) in the fed state to the Cmax of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10.

74. The pharmaceutical composition for use according to any one of claims 63-71, wherein 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.

75. The pharmaceutical composition for use according to any one of claims 63-71, wherein the ratio of the Cmax of the compound of Formula (I) in the fed state to the Cmax of the compound of Formula (I) in the fasted state is about 1.5 to about 3.

76. The pharmaceutical composition for use according to any one of claims 62-75, wherein the subject is a human subject.

77. The pharmaceutical composition for use according to any one of claims 63-69, wherein the pharmaceutical composition exhibits a positive food effect when administered orally.

78. The pharmaceutical composition for use according to claim 77, wherein the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of about 1 to about 4 or about 5 to about 10.

79. The pharmaceutical composition for use according to claim 77, wherein the compound of Formula (I) has a ratio of the Cmax in the fed state to the Cmax in the fasted state of about 1 to about 4 or about 5 to about 10.

80. The pharmaceutical composition for use according to claim 77, wherein the compound of Formula (I) has a ratio of the AUC in the fed state to the AUC in the fasted state of about 1.5 to about 3.

81. The pharmaceutical composition for use according to claim 77, wherein the compound of Formula (I) has a ratio of the Cmax in the fed state to the Cmax in the fasted state of about 1.5 to about 3.

82. The pharmaceutical composition for use according to any one of claims 62-81, wherein the pharmaceutical composition is administered to the subject with a meal.

83. The pharmaceutical composition for use according to claim 82, wherein the meal is a high fat meal.

84. The pharmaceutical composition for use according to claim 82, wherein the meal is a low fat meal.

85. The pharmaceutical composition for use according to any one of claims 82-84, wherein the pharmaceutical composition is administered within about 5 minutes after the start of the meal.

86. The pharmaceutical composition for use according to any one of claims 82-85, wherein the meal is an evening meal.

87. The pharmaceutical composition for use according to any one of claims 82-85, wherein the meal is a morning meal.

88. The pharmaceutical composition for use according to any one of claims 82-87, wherein administering the pharmaceutical composition exhibits a positive food effect.

89. The pharmaceutical composition for use according to claim 88, wherein the positive food effect is measured in terms of Cmax, AUC, or combinations thereof of the compound of Formula (I) when comparing oral administration of the pharmaceutical composition in the fed and fasting states.

90. The pharmaceutical composition for use according to any one of claims 82-89, wherein 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.

91. The pharmaceutical composition for use according to any one of claims 82-90, wherein the ratio of the Cmax of the compound of Formula (I) in the fed state to the Cmax of the compound of Formula (I) in the fasted state is about 1 to about 4 or about 5 to about 10.

92. The pharmaceutical composition for use according to any one of claims 82-89, wherein 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.

93. The pharmaceutical composition for use according to any one of claims 82-89 and 92, wherein the ratio of the Cmax of the compound of Formula (I) in the fed state to the Cmax of the compound of Formula (I) in the fasted state is about 1.5 to about 3.

94. The pharmaceutical composition for use according to any one of claims 62-93, wherein the pharmaceutical composition comprises about 25 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

95. The pharmaceutical composition for use according to any one of claims 62-93, wherein the pharmaceutical composition comprises about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

96. The pharmaceutical composition for use according to any one of claims 62-93, wherein the pharmaceutical composition comprises about 75 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

97. The pharmaceutical composition for use according to any one of claims 62-93, wherein the pharmaceutical composition comprises about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

98. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

99. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

100. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

101. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

102. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

103. The pharmaceutical composition for use according to any one of claims 62-93, 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, based on the weight of the free base.

104. The pharmaceutical composition for use according to any one of claims 62-93, wherein the method comprises administering the pharmaceutical composition twice daily in 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.

105. The pharmaceutical composition for use according to any one of claims 62-93, wherein the method comprises administering the pharmaceutical composition twice daily in 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.

106. The pharmaceutical composition for use according to any one of claims 62-93, wherein the method comprises administering the pharmaceutical composition twice daily in 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.

107. The pharmaceutical composition for use according to any one of claims 62-93, wherein the method comprises administering the pharmaceutical composition twice daily in a dose of about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

108. The pharmaceutical composition for use according to any one of claims 62-107, wherein the subject is concurrently receiving a dose of a glucocorticoid.

109. The pharmaceutical composition for use according to claim 108, wherein the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate.

110. The pharmaceutical composition for use according to claim 108 or 109, wherein the glucocorticoid is cortisol (hydrocortisone).

111. The pharmaceutical composition for use according to claim 108 or 109, wherein the glucocorticoid is cortisone.

112. The pharmaceutical composition for use according to claim 108 or 109, wherein the glucocorticoid is prednisone.

113. The pharmaceutical composition for use according to any one of claims 108-112, wherein the glucocorticoid dose is measured in hydrocortisone equivalents.

114. The pharmaceutical composition for use according to any one of claims 108-113, wherein the glucocorticoid dose is measured as a multiple of the upper limit of normal of physiologic dosing in hydrocortisone equivalents.

115. The pharmaceutical composition for use according to any one of claims 108-114, wherein the glucocorticoid dose is a physiologic dose as measured after a time period of administration of the pharmaceutical composition.

116. The pharmaceutical composition for use according to any one of claims 108-114, wherein the glucocorticoid dose is a physiologic dose of about 4 to about 12 mg / m2 / day as measured after a time period of administration of the pharmaceutical composition.

117. The pharmaceutical composition for use according to any one of claims 108-114, wherein the glucocorticoid dose is a physiologic dose of about 4 to about 9 mg / m2 / day as measured after a time period of administration of the pharmaceutical composition.

118. The pharmaceutical composition for use according to any one of claims 108-114, wherein the glucocorticoid dose is a physiologic dose that is less than about 8 mg / m2 / day as measured after a time period of administration of the pharmaceutical composition.

119. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 10% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition120. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 20% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

121. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 30% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

122. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 40% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

123. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

124. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 60% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

125. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 70% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

126. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by less than about 20% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

127. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by about 20% to about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

128. The pharmaceutical composition for use according to any one of claims 108-118, wherein the glucocorticoid dose of the subject is reduced by greater than about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition.

129. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the pharmaceutical composition.

130. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is reduced by at least about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of 17-hydroxyprogesterone is relative to the level of 17-hydroxyprogesterone prior to administration of the pharmaceutical composition.

131. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition.

132. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is within normal limits after a time period of administration of the pharmaceutical composition.

133. The pharmaceutical composition for use according to any one of claims 62-132, wherein the level of adrenocorticotropic hormone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition.

134. The pharmaceutical composition for use according to any one of claims 62-132, wherein the level of adrenocorticotropic hormone is reduced by at least about 40% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition.

135. The pharmaceutical composition for use according to any one of claims 62-132, wherein the level of adrenocorticotropic hormone is reduced by at least about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition.

136. The pharmaceutical composition for use according to any one of claims 62-132, wherein the level of adrenocorticotropic hormone is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition.

137. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of adrenocorticotropic hormone is within normal limits after a time period of administration of the pharmaceutical composition.

138. The pharmaceutical composition for use according to any one of claims 62-137, wherein the level of androstenedione is reduced by at least about 25% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition.

139. The pharmaceutical composition for use according to any one of claims 62-137, wherein the level of androstenedione is reduced by at least about 30% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition.

140. The pharmaceutical composition for use according to any one of claims 62-137, wherein the level of androstenedione is reduced by at least about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition.

141. The pharmaceutical composition for use according to any one of claims 62-137, wherein the level of androstenedione is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition.

142. The pharmaceutical composition for use according to any one of claims 62-137, wherein the level of androstenedione is within normal limits after a time period of administration of the pharmaceutical composition.

143. The pharmaceutical composition for use according to any one of claims 62-142, wherein the level of testosterone is reduced by at least about 25% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition.

144. The pharmaceutical composition for use according to any one of claims 62-142, wherein the level of testosterone is reduced by at least about 30% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition.

145. The pharmaceutical composition for use according to any one of claims 62-142, wherein the level of testosterone is reduced by at least about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition.

146. The pharmaceutical composition for use according to any one of claims 62-142, wherein the level of testosterone is less than about 1.5 times the upper limit of normal after a time period of administration of the pharmaceutical composition.

147. The pharmaceutical composition for use according to any one of claims 62-142, wherein the level of testosterone is within normal limits after a time period of administration of the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

148. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is reduced by at least about 50% and the level of androstenedione is reduced by at least about 50% after a time period of administration of the pharmaceutical composition, wherein the reduction of the level of 17-hydroxyprogesterone and the level of androstenedione is relative to the level of 17-hydroxyprogesterone and the level of androstenedione prior to administration of the pharmaceutical composition.

149. The pharmaceutical composition for use according to any one of claims 62-128, wherein 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 after a time period of administration of the pharmaceutical composition.

150. The pharmaceutical composition for use according to any one of claims 62-128, wherein the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits after a time period of administration of the pharmaceutical composition.

151. The pharmaceutical composition for use according to any one of claims 108-150, wherein the subject exhibits a decrease in glucocorticoid burden after a time period of administration of the pharmaceutical composition, wherein the decrease in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the pharmaceutical composition.

152. The pharmaceutical composition for use according to claim 151, 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, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor and fertility, is improved after a time period of administration of the pharmaceutical composition, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to administration of the pharmaceutical composition.

153. The pharmaceutical composition for use according to any one of claims 115-152, wherein the time period of administration is at least about 4 weeks.

154. The pharmaceutical composition for use according to any one of claims 115-152, wherein the time period of administration is at least about 24 weeks.

155. The pharmaceutical composition for use according to any one of claims 115-152, wherein the time period of administration is at least about one year.

156. The pharmaceutical composition for use according to any one of claims 62-155, wherein the subject is a pediatric subject.

157. The pharmaceutical composition for use according to claim 156, wherein the pediatric subject is less than or equal to six years old.

158. The pharmaceutical composition for use according to claim 156, wherein the pediatric subject is greater than six years old and less than eleven years old.

159. The pharmaceutical composition for use according to claim 156, wherein the pediatric subject is greater than ten years old and less than fifteen years old.

160. The pharmaceutical composition for use according to claim 156, wherein the pediatric subject is greater than fourteen years old and less than nineteen years old.

161. The pharmaceutical composition for use according to any one of claims 62-155, wherein the subject is an adult subject.

162. The pharmaceutical composition for use according to any one of claims 161, wherein the adult subject is over eighteen years old.

163. The pharmaceutical composition for use according to any one of claims 62-162, wherein the subject is female.

164. The pharmaceutical composition for use according to any one of claims 62-162, wherein the subject is male.

165. The pharmaceutical composition for use according to any one of claims 62-164, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a hydrochloric acid salt or p-toluenesulfonic acid salt.

166. The pharmaceutical composition for use according to any one of claims 62-164, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a p-toluenesulfonic acid crystalline salt.