CRF1 receptor antagonists for treatment of congenital adrenal hyperplasia, pharmaceutical formulations and solid forms thereof

Abstract

Provided are methods related to the treatment of congenital adrenal hyperplasia in a subject in need thereof, the methods comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl) ethyl]-5-methyl-N-propyl-2-alkynyl-1, 3-thiazol-2-amine (Formula I), or a pharmaceutically acceptable salt thereof, and methods of treating congenital adrenal hyperplasia in a subject in need thereof, the methods comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl) ethyl]-5-methyl-N-propyl-2-alkynyl-1, 3-thiazol-2-amine. 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-propyl-2-alkynyl-1, 3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, and their use in the treatment of congenital adrenal hyperplasia (CAH), as well as 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-propyl-2-alkynyl-1, 3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980080385.8, titled "CRF1 Receptor Antagonists, Pharmaceutical Preparations and Solid Forms for the Treatment of Congenital Adrenal Hyperplasia", filed on December 06, 2019. Technical Field

[0002] The present disclosure relates to 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof for the treatment of congenital adrenal hyperplasia (CAH). The present disclosure also relates to pharmaceutical preparations 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

[0004] Classic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders, which are due to a deficiency of the enzyme 21-hydroxylase that results in an enzyme deficiency that alters adrenal steroid production, a condition that results in little or no cortisol biosynthesis. One clinical manifestation of cortisol deficiency 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 into alternative pathways. Most notably, the shunting of androgens results in virilization of females and other developmental complications, and the excessive accumulation of ACTH is associated with the formation of testicular adrenal rest tumors in males. In addition, because the same enzyme (21-hydroxylase) is used in the biosynthetic pathway of mineralocorticoids, many of these patients suffer from aldosterone deficiency, which can lead to dehydration and death due to salt loss. Based on newborn screening, the incidence of classic 21-hydroxylase deficiency type CAH in the general population in the United States has been recorded 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).

[0005] Pediatric patients from birth to adolescence, particularly females, appear to be the most susceptible group of patients with CAH and represent the patient subgroup with the greatest 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). Excess androgen production in these young patients results in premature puberty and adrenarche, changes in the pattern of skeletal maturation, short stature due to early growth plate fusion, and significant hirsutism and acne problems. Although survival is appropriately ensured by steroid replacement strategies based on physiological administration of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these doses are generally insufficient to suppress the accumulation of ACTH and the overproduction of progesterone and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). In fact, the uncontrolled symptoms of androgen excess have a significant impact on the daily functioning and development of these patients.

[0006] Currently, exogenous corticosteroids are the standard of care for treating patients with classical CAH. This treatment is used to correct cortisol deficiency and reduce elevated ACTH levels and androgen excess. However, the dose and duration of steroids required to suppress ACTH are typically much higher than the normal physiological levels used solely for cortisol replacement (such 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 rate, and reduced 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).

[0007] Corticotropin - releasing factor (CRF) is a hypothalamic hormone that is released directly into the pituitary portal vasculature and acts on the specific corticotropin - releasing factor 1 (CRF1) receptor on corticotropin in the anterior pituitary to stimulate the release of ACTH. It has been shown that blockade of these receptors in animals and humans reduces the release of ACTH. Thus, compounds that block the CRF1 receptor can directly inhibit the excessive ACTH release that occurs in CAH, allowing normalization of androgen production while using lower, more physiological doses of hydrocortisone.

[0008] Compounds of formula (I):

[0009]

[0010] 4-(2-chloro-4-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 compounds 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 compounds of formula (I) are low solubility compounds with low bioavailability. Partially due to their low solubility, it has proven difficult to attempt to formulate the compounds of formula (I), especially for formulations suitable for pediatric administration.

[0011] Accordingly, there is a need for the treatment of CAH that avoids the serious complications associated with corticosteroid therapy. There is also a need for formulations of the compounds of formula (I) with increased bioavailability and for formulations of the compounds of formula (I) suitable for pediatric administration. The formulations and methods of the present invention help to address these and other needs. SUMMARY OF THE INVENTION

[0012] The present invention provides pharmaceutical compositions comprising:

[0013] (a) a compound of formula (I):

[0014]

[0015] or a pharmaceutically acceptable salt thereof; and

[0016] (b) one or more of an oil phase vehicle, an emulsifier, a nonionic surfactant, and a solubilizer.

[0017] The present invention provides pharmaceutical compositions in an oral solution dosage form comprising:

[0018] (a) a compound of formula (I):

[0019]

[0020] or a pharmaceutically acceptable salt thereof;

[0021] (b) one or more of a sweetening agent, an antioxidant, and a flavoring agent; and

[0022] (c) a liquid vehicle.

[0023] The present invention also provides the pharmaceutical compositions of the present disclosure (e.g., the pharmaceutical compositions in an oral solution dosage form of the present disclosure) for use in treatment, e.g., for any method disclosed herein.

[0024] The present invention provides methods for treating congenital adrenal hyperplasia (CAH), including 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 of formula (I):

[0025]

[0026]

[0027] or a pharmaceutically acceptable salt thereof.

[0028] The present invention also provides a compound for use in a method for treating congenital adrenal hyperplasia in an individual, 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.

[0029] The present invention also provides the use of a compound in the manufacture of a medicament for use in a method for treating congenital adrenal hyperplasia in an individual, 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.

[0030] The present invention provides a method for treating congenital adrenal hyperplasia in an individual in need thereof, the method 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 individual.

[0031] The present invention also provides a compound or a pharmaceutically acceptable salt thereof for use in a method of treating congenital adrenal hyperplasia in an individual, said compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione in the individual.

[0032] The present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia in an individual, said compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione in the individual.

[0033] In some embodiments, a decrease in the level of any biomarker is determined by comparing the level of the biomarker measured during the rhythmic release on the day prior to 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 and the level of the biomarker measured during the rhythmic release on the day of administration of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof. In some embodiments, the rhythmic release occurs between 2:00 am and 10:00 am.

[0034] 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 rhythmic release of the biomarker.

[0035] 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%.

[0036] 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%.

[0037] 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%.

[0038] 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%.

[0039] In some embodiments, 4 - (2 - chloro - 4 - methoxy - 5 - methylphenyl)-N - [(1S)-2 - cyclopropyl - 1 - (3 - fluoro - 4 - methylphenyl)ethyl]-5 - methyl - N - prop - 2 - yn - 1 - yl - 1,3 - thiazol - 2 - amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of the free base of 4 - (2 - chloro - 4 - methoxy - 5 - methylphenyl)-N - [(1S)-2 - cyclopropyl - 1 - (3 - fluoro - 4 - methylphenyl)ethyl]-5 - methyl - N - prop - 2 - yn - 1 - yl - 1,3 - thiazol - 2 - amine.

[0040] In some embodiments, 4 - (2 - chloro - 4 - methoxy - 5 - methylphenyl)-N - [(1S)-2 - cyclopropyl - 1 - (3 - fluoro - 4 - methylphenyl)ethyl]-5 - methyl - N - prop - 2 - yn - 1 - yl - 1,3 - thiazol - 2 - amine is administered in free - base form.

[0041] Provided herein are methods for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in an individual with classical congenital adrenal hyperplasia, the method comprising administering 4 - (2 - chloro - 4 - methoxy - 5 - methylphenyl)-N - [(1S)-2 - cyclopropyl - 1 - (3 - fluoro - 4 - methylphenyl)ethyl]-5 - methyl - N - prop - 2 - yn - 1 - yl - 1,3 - thiazol - 2 - amine or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of androstenedione in the individual. In some embodiments, the growth impairment is selected from one or more of accelerated height velocity, accelerated weight velocity, or accelerated bone age.

[0042] The present invention also provides 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 an individual suffering from classical congenital adrenal hyperplasia, wherein the compound or its pharmaceutically acceptable salt is administered in an amount sufficient to reduce the level of androstenedione in the individual.

[0043] The present invention also provides the use of a compound 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 an individual suffering from classical congenital adrenal hyperplasia, the compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, wherein the compound or its pharmaceutically acceptable salt is administered in an amount sufficient to reduce the level of androstenedione in the individual.

[0044] 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%.

[0045] The present invention provides a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in an individual suffering from congenital adrenal hyperplasia, the method comprising administering to the individual 4-(2-chloro-4-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.

[0046] The present invention also provides a compound for use in a method of reducing the level of one or more biomarkers of congenital adrenal hyperplasia in an individual suffering from congenital adrenal hyperplasia, 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.

[0047] The present invention also provides the use of a compound 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 an individual suffering from congenital adrenal hyperplasia, said compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine.

[0048] 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.

[0049] The present invention provides a method of controlling congenital adrenal hyperplasia by reducing the dose of corticosteroid administered to an individual suffering from congenital adrenal hyperplasia, said method comprising administering to said individual 4-(2-chloro-4-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.

[0050] The present invention also provides 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 dose of corticosteroid administered to an individual suffering from congenital adrenal hyperplasia.

[0051] The present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of reducing the dose of corticosteroid administered to an individual suffering from congenital adrenal hyperplasia, said compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine.

[0052] The present invention provides a method for reducing the severity of one or more side effects of glucocorticoid therapy in an individual with congenital adrenal hyperplasia, the method comprising administering to the individual 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the side effects are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, 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, erosion, striae, delayed wound healing, easy bruising, acne, hirsutism, alopecia, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive deficit, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, susceptibility to infection, and reactivation of latent infections.

[0053] The present invention also provides a compound for use in a method for reducing the severity of one or more side effects of glucocorticoid therapy in an individual with congenital adrenal hyperplasia, 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 side effects are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, 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, erosion, striae, delayed wound healing, easy bruising, acne, hirsutism, alopecia, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive deficit, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, susceptibility to infection, and reactivation of latent infections.

[0054] The present invention also provides the use of a compound 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 therapy in an individual suffering from congenital adrenal hyperplasia, said compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, wherein said side effects are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, 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, alopecia, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive deficits, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, increased susceptibility to infection and reactivation of latent infections.

[0055] 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 in an amount sufficient to reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% compared to the level prior to administration.

[0056] 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 in an amount sufficient to reduce the level of androstenedione by at least 30% compared to the level prior to administration.

[0057] 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 in an amount sufficient to (a) reduce the level of 17-hydroxyprogesterone (17-OHP) by at least 50% compared to the level prior to administration; and (b) reduce the level of androstenedione by at least 30% compared to the level prior to administration.

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

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

[0060] 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-yn-1-yl-1,3-thiazol-2-amine is administered in free base form.

[0061] Provided herein are methods of treating congenital adrenal hyperplasia in an individual, 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 individual;

[0062] (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy individual not having congenital adrenal hyperplasia; and

[0063] (iii) if the individual is determined to have an elevated level of the one or more biomarkers, administering to the individual 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof.

[0064] The present invention also provides 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 an individual, the method comprising

[0065] (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 individual;

[0066] (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy individual not suffering from congenital adrenal hyperplasia; and

[0067] (iii) if the individual is determined to have an elevated level of the one or more biomarkers, administering to the individual 4-(2-chloro-4-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.

[0068] The present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia in an individual, the compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, wherein the method comprises:

[0069] (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 individual;

[0070] (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy individual not suffering from congenital adrenal hyperplasia; and

[0071] (iii) If the individual is determined to have an elevated level of one or more of said biomarkers, administer to the individual 4-(2-chloro-4-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.

[0072] In some embodiments, the method further comprises (iv) 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, measuring the level of one or more of said biomarkers in a biological sample obtained from the individual, and determining whether the individual has a reduced level of one or more of said biomarkers as compared to the measurement of step (i). In some embodiments, the method further comprises (v) if the individual has a reduced level of one or more of said biomarkers, continuing to administer 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, steps (i) and (iv) are performed on biological samples collected from an individual in a similar manner and within the same time window. In some embodiments, steps (i) and (iv) are performed on biological samples collected from the individual within a time window from 2:00 am to 10:00 am. In some embodiments, steps (i) and (iv) are performed on biological samples collected from the individual within a time window from 6:00 am to 10:00 am.

[0074] 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.

[0075] In some embodiments, steps (i) and (iv) comprise measuring the levels of (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione.

[0076] 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.

[0077] In some embodiments, step (i) comprises measuring the level of androstenedione, wherein when it is greater than 200 ng / dL, the level of androstenedione is elevated.

[0078] 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-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 25 mg to about 150 mg of the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn-1-yl-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-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered once daily in an amount equivalent to about 50 mg or about 100 mg of the 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn-1-yl-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-yn-1-yl-1,3-thiazol-2-amine is administered in free base form.

[0079] Provided herein are methods for treating congenital adrenal hyperplasia (CAH) in an individual in need thereof, the methods comprising administering to the individual 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-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the individual is in a fed state.

[0080] Also provided herein are methods for treating congenital adrenal hyperplasia (CAH) in an individual, the non-compound being 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the individual is in a fed state.

[0081] The present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating congenital adrenal hyperplasia (CAH) in an individual, wherein the compound 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, and wherein the individual is in a fed state.

[0082] 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 individual together 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% carbohydrates. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the 4-(2-chloro-4-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.

[0083] 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 individual together 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% carbohydrates. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the 4-(2-chloro-4-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.

[0084] In some embodiments, 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 exhibits a positive food effect. In some embodiments, 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 state and the fasted state, the positive food effect is measured in terms of C max , AUC, or a combination thereof.

[0085] In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasted state is from about 5 to about 10. In some embodiments, the C max in the fed state to the C max in the fasted state is from about 5 to about 10.

[0086] Methods for reducing the glucocorticoid burden in an individual are provided herein, such as as measured after administration of a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the reduction in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0087] Compounds for use in methods for reducing the glucocorticoid burden in an individual are also provided herein, which are 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the reduction in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0088] Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method for reducing the glucocorticoid burden in an individual is also provided herein, wherein the compound 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, and wherein the reduction in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0089] The present invention provides a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility in an individual suffering from classical congenital adrenal hyperplasia, the method comprising administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, wherein the symptoms are improved after administration of the compound or its pharmaceutically acceptable salt for a period of time, and wherein the improvement of the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound or its pharmaceutically acceptable salt.

[0090] The present invention also provides a compound for use in a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility in an individual suffering from classical congenital adrenal hyperplasia, 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 symptoms are improved after administration of the compound or its pharmaceutically acceptable salt for a period of time, and wherein the improvement of the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound or its pharmaceutically acceptable salt.

[0091] The present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method for improving one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility in an individual suffering from classical congenital adrenal hyperplasia, wherein the compound 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, and wherein the symptoms are improved after administration of the compound or a pharmaceutically acceptable salt thereof for a period of time, and wherein the improvement of the one or more symptoms is relative to the state of the one or more symptoms before administration of the compound or a pharmaceutically acceptable salt thereof.

[0092] The present invention also provides a compound for use in treatment, for example for any method disclosed herein, 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.

[0093] The present invention also provides the use of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for any method disclosed herein.

[0094] The present invention also provides 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 of formula (I) or a pharmaceutically acceptable salt thereof:

[0095]

[0096] and a polymer. In some embodiments, the polymer is selected from neutral polymers, enteric polymers, and pyrrolidone polymers. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is from about 1:9 to about 1:1.

[0097] In some embodiments, the polymer is a neutral polymer. In some embodiments, the neutral polymer is selected from hydroxypropyl methylcellulose (HPMC) and hydroxyethylcellulose (HEC).

[0098] In some embodiments, the polymer is an enteric polymer. In some embodiments, the enteric polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), amino methacrylate copolymer, ammonium alkyl methacrylate copolymer, and methacrylic acid copolymer.

[0099] In some embodiments, the polymer is a pyrrolidone polymer. In some embodiments, the pyrrolidone polymer is selected from polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone vinyl acetate (PVP / VA). In some embodiments, the pyrrolidone polymer is PVP / VA. In some embodiments, the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of about 40:60 to about 60:40 by weight. In some embodiments, the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of about 60:40 by weight. In some embodiments, the copolymer has the following structure:

[0100]

[0101] 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.

[0102] Provided herein are spray-dried dispersions 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 of formula (I) or a pharmaceutically acceptable salt thereof:

[0103]

[0104] and a polymer, which is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the following structure:

[0105]

[0106] wherein the value of n is about 1 to about 2 times the value of m, and the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of about 60:40 by weight; and wherein the weight ratio of the compound of formula (I) to the copolymer is about 1:1 to about 1:9.

[0107] In some embodiments of the spray-dried dispersions of the present disclosure, the compound of formula (I) and the polymer together form uniform particles. In some embodiments, the particles have a particle size distribution D of from about 5 μm to about 100 μm 50 。In some embodiments, the particles have a particle size distribution D of from about 10 μm to about 50 μm 50 。In some embodiments, the particles have a particle size distribution D of from about 15 μm to about 30 μm 50 。

[0108] 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.

[0109] In some embodiments, the particles have a residual solvent content of less than about 2 wt%. In some embodiments, the particles have a residual solvent content of less than about 1 wt%. In some embodiments, the particles have a residual solvent content of about 0.5 wt% or less.

[0110] In some embodiments, the compound of formula (I) in the dispersion is substantially amorphous.

[0111] Also provided herein is a method for preparing the spray-dried dispersions of the present disclosure, comprising: dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof and a polymer in an organic solvent to form a solution; and spray-drying the solution to produce the spray-dried dispersion, wherein the spray-drying forms uniform particles of the compound of formula (I) and the polymer.

[0112] In some embodiments, the method includes removing the organic solvent by drying the spray-dried dispersion after forming the spray-dried dispersion. In some embodiments, the spray-dried dispersion is dried using a convective tray dryer. In some embodiments, the organic solvent is acetone.

[0113] In some embodiments, the inlet temperature of the spray dryer is from about 60 °C to about 80 °C. In some embodiments, the inlet temperature of the spray dryer is about 72 °C.

[0114] In some embodiments, the outlet temperature of the spray dryer is from about 25 °C to about 45 °C. In some embodiments, the outlet temperature of the spray dryer is about 35 °C.

[0115] In some embodiments, the uniform particles comprise a tapped density of less than about 0.2 g / mL. In some embodiments, the uniform particles comprise a tapped density of less than about 0.15 g / mL.

[0116] In some embodiments, the uniform particles comprise a bulk density of less than about 0.3 g / mL. In some embodiments, the uniform particles comprise a bulk density of less than about 0.25 g / mL.

[0117] Also provided herein are pharmaceutical compositions comprising the spray-dried dispersions of the present disclosure and one or more pharmaceutically acceptable excipients. In some embodiments, the spray-dried dispersion is present in the composition in an amount of about 20% w / w to about 90% w / w. In some embodiments, the spray-dried dispersion is present in the composition in an amount of about 40% w / w to about 80% w / w.

[0118] In some embodiments, the pharmaceutical excipients are selected from fillers, lubricants, and combinations thereof. In some embodiments, the fillers are selected from binders, diluents, disintegrants, glidants, surfactants, and combinations thereof.

[0119] In some embodiments, the pharmaceutical composition is formulated into a unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg 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.

[0120] In some embodiments, the pharmaceutical composition is formulated as a tablet, capsule, sachet, powder, granule, coated granule, coated tablet, enteric-coated tablet, enteric-coated capsule, melt strip, or melt film. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is coated.

[0121] In some embodiments, the spray-dried dispersion is formulated for oral administration and exhibits a positive food effect when orally administered. In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasted state of the spray-dried dispersion is about 5 to about 10. In some embodiments, wherein the spray-dried dispersion has a C max in the fed state to the C max in the fasted state is about 5 to about 10.

[0122] The present disclosure also provides a method for preparing a pharmaceutical composition, which includes combining the spray-dried dispersion of the present disclosure with one or more pharmaceutically acceptable excipients.

[0123] The present disclosure also provides a method for treating congenital adrenal hyperplasia (CAH) in an individual in need thereof, which includes administering to the individual a therapeutically effective amount of the spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising the spray-dried dispersion of the present disclosure.

[0124] The present disclosure also provides the spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising the spray-dried dispersion of the present disclosure for use in a method for treating congenital adrenal hyperplasia (CAH) in an individual.

[0125] The present disclosure also provides the use of the spray-dried dispersion of the present disclosure in the manufacture of a medicament for use in a method for treating congenital adrenal hyperplasia (CAH) in an individual.

[0126] In some embodiments, the spray-dried dispersion or the pharmaceutical composition is administered to an individual in a fed state. In some embodiments, the spray-dried dispersion or the pharmaceutical composition is administered to the individual together with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement containing about 1000 to about 2000 calories per liter and having a fat content greater than about 30%. In some embodiments, the nutritional composition is a liquid dietary supplement containing 1500 calories per liter, with a calorie distribution of 14.7% protein, 32% fat, and 53.3% carbohydrates. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the spray-dried dispersion or the pharmaceutical composition.

[0127] In some embodiments, administering the spray-dried dispersion or the pharmaceutical composition exhibits a positive food effect. In some embodiments, when comparing oral administration of the spray-dried dispersion or the pharmaceutical composition in a fed state and a fasting state, the positive food effect is measured in terms of C max , AUC, or a combination thereof. In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasting state is about 5 to about 10. In some embodiments, the C max in the fed state to the C max in the fasting state is about 5 to about 10. In some embodiments, the ratio of the AUC in the fed state to the AUC in the fasting state is about 10 to about 20. In some embodiments, the Cmax and C in the fasting state max has a ratio of about 10 to about 20.

[0128] In some embodiments of the disclosed methods, the individual is a pediatric individual.

[0129] Also provided herein are spray-dried dispersions of the present disclosure for use in treating, e.g., any method disclosed herein, or pharmaceutical compositions comprising a spray-dried dispersion of the present disclosure.

[0130] Also provided herein is the use of a spray-dried dispersion of the present disclosure for the manufacture of a medicament for any method disclosed herein.

[0131] Also provided herein is a method of treating congenital adrenal hyperplasia (CAH) in an individual in need thereof, comprising administering to the individual a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0132] Also provided herein is a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in a method of treating congenital adrenal hyperplasia (CAH) in an individual.

[0133] Also provided herein is the use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for a method of treating congenital adrenal hyperplasia (CAH) in an individual, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0134] Also provided herein is a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating, e.g., any method disclosed herein.

[0135] Also provided herein is the use of a pharmaceutical composition of the present disclosure for the manufacture of a medicament for any method disclosed herein, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0136] Also provided herein is a method of improving gastrointestinal absorption of a compound of formula (I) in an individual, comprising orally administering to the individual 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) not formulated as a spray-dried dispersion.

[0137] The present disclosure also provides a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising the spray-dried dispersion of the present disclosure, for use in a method of improving gastrointestinal absorption of a compound of formula (I) in an individual, wherein the improvement is relative to oral administration of the compound of formula (I) not formulated as a spray-dried dispersion.

[0138] The present disclosure also provides the 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 an individual, wherein the improvement is relative to oral administration of the compound of formula (I) not formulated as a spray-dried dispersion.

[0139] In some embodiments, the individual is a pediatric individual.

[0140] The present disclosure also provides a method of improving oral bioavailability of a compound of formula (I) in an individual, comprising orally administering to the individual a therapeutically effective amount of a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising the spray-dried dispersion of the present disclosure, wherein the improvement is relative to oral administration of the compound of formula (I) not formulated as a spray-dried dispersion

[0141] The present disclosure also provides a spray-dried dispersion of the present disclosure or a pharmaceutical composition comprising the spray-dried dispersion of the present disclosure, for use in a method of improving oral bioavailability of a compound of formula (I) in an individual, wherein the improvement is relative to oral administration of the compound of formula (I) not formulated as a spray-dried dispersion.

[0142] The present disclosure also provides the 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 an individual, wherein the improvement is relative to oral administration of the compound of formula (I) not formulated as a spray-dried dispersion.

[0143] In some embodiments, the individual is a pediatric individual.

[0144] The present disclosure also provides 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-toluenesulfonate.

[0145] The present disclosure also provides 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-toluenesulfonate, for use in therapy, for example for any of the methods disclosed herein.

[0146] The present invention also provides the use of the crystalline salt in the manufacture of a medicament for any of the methods disclosed herein, said crystalline salt being 4-(2-chloro-4-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-toluenesulfonate.

[0147] Other features and advantages of the methods, processes, formulations and uses provided herein will be apparent from the following detailed description, the drawings and the claims.

[0148] Description of the Drawings

[0149] Figure 1 Shows the dissolution performance of several spray-dried dispersion formulations in phosphate-buffered saline (PBS) (pH 6.5) with 0.5 wt% simulated intestinal fluid (SIF).

[0150] Figure 2 Shows the vertical membrane flux unit integrated in the μDiss Profiler TM for membrane flux determination.

[0151] Figure 3 Shows the non-settling dissolution data of several spray-dried dispersion formulations and the compound of formula (I) in a PBS solution (pH 6.5) with 0.5 wt% SIF.

[0152] Figure 4 Is a graph showing the membrane flux of the compound of formula (I) and various spray-dried dispersion formulations at a dose of 1 mg / mL GB / IB 0.5 wt% SIF as a function of time. The solid line represents the flux (μg min -1 cm -2 ), and the dashed line represents the concentration (μg / mL) in 0.5% SIF.

[0153] Figure 5 Is a flow chart of a spray-drying manufacturing method for preparing a 1000 g SDD batch containing 25% of the compound of formula (I) and 75% PVP / VA 64.

[0154] Figure 6A and Figure 6B Is a line graph showing the pharmacokinetic results of a bioavailability and food effect study in dogs. Figure 6A Shows the results from cohort 1 and Figure 6B shows the results from cohort 2.

[0155] Figure 7Is 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 individuals.

[0156] Figure 8A And Figure 8B Is a line graph showing the mean plasma concentration-time curves of the compound of formula (I) in healthy adult individuals under fasting and fed conditions, respectively.

[0157] Figures 9A to 9C Is a spaghetti plot of the pharmacokinetics of the compound of formula (I) in healthy adult individuals under fasting and fed conditions. Figure 9A Shows the AUC 0-tlast Value. Figure 9B Shows the AUC 0-∞ Value. Figure 9C Shows the C max Value.

[0158] Figure 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 individuals.

[0159] Figure 11 Shows the study design of a Phase 2 study of the compound of formula (I) in adult individuals with congenital adrenal hyperplasia.

[0160] Figure 12A And Figure 12B Shows a plot of the arithmetic means of adrenocorticotropic hormone (ACTH) ( Figure 12A ) and 17-hydroxyprogesterone (17-OHP) ( Figure 12B ) for all 8 individuals in cohort 1 plotted at each time point of pre-treatment baseline (circles), day 1 (squares) and day 14 (triangles).

[0161] Figure 13A And Figure 13B Shows a plot of the arithmetic means of androstenedione ( Figure 13A ) and testosterone ( Figure 13B ) for all 8 individuals in cohort 1 plotted at each time point of pre-treatment baseline (circles), day 1 (squares) and day 14 (triangles).

[0162] Figure 14A And Figure 14B Shows the decrease in ACTH at the time points 8 hours, 10 hours and 12 hours after dosing. Figure 14A Shows the value at each time point compared to baseline. Figure 14B Shows the mean across all three time points.

[0163] Figure 15A and Figure 15B shows the reduction of 17 - OHP at the time points of 8 hours, 10 hours, and 12 hours after drug administration. Figure 15A shows the values at each time point compared to the baseline. Figure 15B shows the average value across all three time points.

[0164] Figure 16A and Figure 16B shows the reduction of androstenedione at the time points of 8 hours, 10 hours, and 12 hours after drug administration. Figure 16A shows the values at each time point compared to the baseline. Figure 16B shows the average value across all three time points.

[0165] Figure 17A shows the average plasma ACTH blood concentration after administering 50 mg of the compound of formula (I) once daily at bedtime (cohort 1; n = 8). Error bars represent the standard error of the mean for each morning window time point. Normal range of ACTH: 6 to 58 pg / mL for females; 7 to 69 pg / mL for males.

[0166] Figure 17B shows the average serum 17 - OHP blood concentration after administering 50 mg of the compound of formula (I) once daily at bedtime (cohort 1; n = 8). Error bars represent the standard error of the mean for each morning window time point. Normal range of 7 - OHP: < 207 ng / dL for females; < 139 ng / dL for males.

[0167] Figure 17C : shows the average serum androstenedione blood concentration after administering 50 mg of the compound of formula (I) once daily at bedtime (cohort 1; n = 8). Error bars represent the standard error of the mean for each morning window time point. Normal range of androstenedione: 26 to 214 ng / mL for females; 33 to 134 ng / mL for males.

[0168] Figure 18A shows the average plasma ACTH blood concentration after administering 50 mg of the compound of formula (I) once daily at bedtime (cohort 2; n = 4). Error bars represent the standard error of the mean for each morning window time point. Normal range of ACTH: 6 to 58 pg / mL for females; 7 to 69 pg / mL for males.

[0169] Figure 18BShows the mean serum 17-OHP blood concentration after administration of 50 mg of the compound of formula (I) once daily at bedtime (cohort 2; n = 4). Error bars represent the standard error of the mean for each morning window time point. Normal range for 7-OHP: < 207 ng / dL for females; < 139 ng / dL for males.

[0170] Figure 18C : Shows the mean serum androstenedione blood concentration after administration of 50 mg of the compound of formula (I) once daily at bedtime (cohort 2; n = 4). Error bars represent the standard error of the mean for each morning window time point. Normal range for androstenedione: 26 to 214 ng / mL for females; 33 to 134 ng / mL for males.

[0171] Figure 19A Shows the mean plasma ACTH blood concentration after administration of 100 mg of the compound of formula (I) with dinner (cohort 3). Error bars represent the standard error of the mean for each morning window time point. Normal range for ACTH: 6 to 58 pg / mL for females; 7 to 69 pg / mL for males.

[0172] Figure 19B Shows the mean serum 17-OHP blood concentration after administration of 100 mg of the compound of formula (I) with dinner (cohort 3). Error bars represent the standard error of the mean for each morning window time point. Normal range for 17-OHP: < 207 ng / dL for females; < 139 ng / dL for males.

[0173] Figure 19C Shows the mean serum androstenedione blood concentration after administration of 100 mg of the compound of formula (I) with dinner (cohort 3). Error bars represent the standard error of the mean for each morning window time point. Normal range for androstenedione: 26 to 214 ng / mL for females; 33 to 134 ng / mL for males.

[0174] Figure 20 Is a scheme showing the manufacturing method for forming capsules of the 50 mg compound of formula (I).

[0175] Figure 21 Is an alternative scheme showing the manufacturing method for forming capsules of the 50 mg compound of formula (I).

[0176] Figure 22A and Figure 22B Shows a scheme of the manufacturing method for forming SDD particles of the compound of formula (I).

[0177] Figure 23 Is a scheme showing the manufacturing method for forming 50 mg / nL liquid formulation 1 of the compound of formula (I).

[0178] Figure 24 It is a scheme showing a method for manufacturing a 50 mg / nL liquid formulation 2 of a compound of formula (I).

[0179] Figure 25 It is an XRPD spectrum of crystalline form I of the free base of the compound of formula (I).

[0180] Figure 26 It is a DSC spectrum of crystalline form I of the free base of the compound of formula (I).

[0181] Figure 27 It is an XRPD spectrum of crystalline form 1 of the tosylate of the compound of formula (I).

[0182] Figure 28 It is a DSC and TGA spectrum of crystalline form 1 of the tosylate of the compound of formula (I). Detailed Description

[0183] 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 of formula (I):

[0184]

[0185] or a pharmaceutically acceptable salt thereof, is a selective CRF1 receptor antagonist that has been found to be effective in treating congenital adrenal hyperplasia. Specifically, the compounds of formula (I) have been found to effectively reduce several biomarkers associated with congenital adrenal hyperplasia.

[0186] Neonatal screening for CAH is performed by immunoassay to measure 17-OHP levels in heel capillary blood samples obtained within the first 72 hours of life. The 17-OHP in blood samples is analyzed by a commercially available dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA; PerkinElmer, Waltham Massachusetts) (White et al., J. Pediatr. 163:10-12 (2013)). Second-tier screening tests using biochemical testing methods and molecular genetic testing methods (performed between day 8 and day 14 of life) are employed in nine states in the United States and are strongly recommended in an additional five states. Biochemical methods include immunoassays with organic solvent extraction or liquid chromatography followed by tandem mass spectrometry to measure the steroid ratios of 17-OHP, androstenedione, 21-deoxycortisol, and cortisol (see, e.g., Speiser et al., Int. J. Pediatr. Endocrinol. 2010:494173, 2010). Genetic screening looks for CYP21A2 mutations associated with CAH. Although not widely adopted in the United States, adding a second screening can improve the sensitivity of the overall screening process, where the sensitivity of the first screening alone is approximately 72%.

[0187] In the absence of neonatal screening results, female infants with classic CAH are usually identified due to ambiguous genitalia. Males have normal genitalia at birth and thus cannot be diagnosed unless neonatal screening or other medical complications draw attention. Infants who are initially undiagnosed with CAH and develop salt-losing disease are subsequently diagnosed in the first few weeks of life in the setting of poor weight gain, vomiting, hyperkalemia, and hyponatremia.

[0188] Treatment of CAH is based on normalizing hormone and steroid levels using various medications from infancy to adulthood according to the diagnosis. Glucocorticoids are the current standard treatment for CAH and are used to correct endogenous cortisol deficiency and reduce elevated ACTH levels from the pituitary gland. Different from the treatment of Addison's disease (adrenocortical insufficiency), in which cortisol replacement is sufficient, the treatment of CAH must also reduce ACTH production to control subsequent androgen excess. Thus, the goals of glucocorticoid treatment include cortisol replacement and ACTH suppression to prevent virilization and menstrual disorders in females and to suppress testicular adrenal rest tumors in males. Mineralocorticoid replacement is needed to achieve normal plasma renin activity to maintain normal blood pressure, electrolyte balance, and volume status in those patients with salt-losing CAH.

[0189] The glucocorticoid treatment regimen must support normal physiological functions and should also ensure sufficient cortisol availability during events that can cause strong stress responses (e.g., concurrent illness, exercise, hypotension). Careful monitoring is also necessary to avoid iatrogenic Cushing’s syndrome due to over-treatment with glucocorticoids in an attempt to fully suppress androgen production or the development of Addison’s syndrome due to under-treatment.

[0190] Over-treatment with mineralocorticoids can cause hypertension, whereas under-treatment can lead to hypotension, salt wasting, fatigue, and increased requirement for glucocorticoids. Typical laboratory tests for monitoring treatment efficacy include measurement of plasma concentrations of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes.

[0191] Adult patients with CAH have an increased incidence 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 group of pediatric and adult CAH patients (n = 244) showed that patients were prescribed a variety of glucocorticoid treatment regimens but frequently suffered from poor hormonal control and the aforementioned adverse outcomes (see, e.g., Finkielstain et al., J. Clin. Endocrinol. Metab. 97(12):4429-38 (2012)).

[0192] Treatment of CAH involves attempting to normalize cortisol deficiency with glucocorticoids (usually hydrocortisone for children, but usually more potent agents with a narrow therapeutic index, such as dexamethasone, for adults), and, if salt wasting is required, mineralocorticoids (usually fludrocortisone). However, the glucocorticoid doses required to achieve adequate suppression of excess androgens are generally much higher than the normal physiological doses used for cortisol replacement alone in patients with Addison's disease. This increased glucocorticoid exposure can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, and reduced 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 herein by reference in its entirety.

[0193] Corticotropin-releasing factor (CRF) was isolated from sheep hypothalamus and identified as a 41-amino acid peptide. CRF has been found to cause significant changes in endocrine, neural, and immune system functions. CRF is believed to be the major physiological regulator of basal and stress-induced release of adrenocorticotropic hormone ("ACTH"), β-endorphin, and other proopiomelanocortin (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 corticotroph cells of the anterior pituitary via binding to the CRF1 receptor (a member of the class B family of G-protein coupled receptors).

[0194] Due to the physiological importance of CRF, the development of small molecules with significant CRF1 receptor binding activity and the ability to antagonize the biological activity of the CRF1 receptor remains a desirable goal and is the subject of current research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and drug abuse.

[0195] Under the control of hypothalamic corticotropin-releasing factor (CRF), the pituitary hormone ACTH stimulates cholesterol uptake and drives the synthesis of pregnenolone, thereby initiating steroidogenesis in the adrenal gland. The adrenal cortex consists of three zones that produce different types of hormones, and many hormones are driven by cholesterol mobilized by ACTH through this pathway. Deficiency of these enzymes due to mutation or deletion causes an increase in substrate concentration. In the most common form of CAH caused by mutation or deletion of the 21-hydroxylase gene (CYP21A2), the adrenal gland produces potent androgens due to the accumulation of steroid precursors, progesterone, and 17-hydroxyprogesterone (17-OHP). In these cases, the plasma levels of 17-OHP can reach 10 to 1000 times the normal concentration. These increases lead to the overproduction of androgens, especially androstenedione, testosterone, and dihydrotestosterone, which causes virilization in females. In addition, 21-hydroxylase deficiency in CAH causes insufficient biosynthesis of glucocorticoids and mineralocorticoids, especially cortisol and aldosterone. Cortisol is a key negative feedback regulator of CRF secretion in the hypothalamus and ACTH release in the pituitary gland. Insufficient synthesis and release of glucocorticoids eliminate the inhibition of the hypothalamus and pituitary gland, which causes an increase in ACTH levels. Excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis, leading to adrenal hyperplasia.

[0196] Definitions

[0197] 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 this disclosure; other suitable methods and materials known in the art may 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) shall prevail.

[0198] In DSC, TGA, or T g The term "about" (reported in degrees Celsius) before a value of DSC, TGA, or T has an allowable variability of ±5 °C. In all other cases, unless otherwise stated, the term "about" before a specified value includes the specified value and also includes ±20% of the specified value, and more specifically includes ±10%, ±5%, ±2%, and ±1% of the specified value.

[0199] To provide a more concise description, some quantitative expressions herein are stated as a range from about amount X to about amount Y. It should be understood that when a range is stated, the range is not limited to the upper and lower limits stated, but includes the entire range from about amount X to about amount Y, or any range therein.

[0200] "Room temperature" or "RT" refers to the ambient temperature in a typical laboratory, which is usually about 25 °C.

[0201] "Spray drying" refers to a method of producing dry powder from a solution or slurry. The solution or slurry is atomized or rapidly dried with hot gas (e.g., air or nitrogen), which causes the solvent to evaporate rapidly and uniformly. "Spray-dried dispersion" refers to the powder obtained by the spray drying method.

[0202] 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 agents, absorption delaying agents, etc., which are not biologically or otherwise undesirable. The use of such media and agents for active pharmaceutical substances is well known in the art. Their use in therapeutic formulations is contemplated unless any conventional medium or agent is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the formulations. Additionally, for example, various excipients 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 regarding 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 Edition, The McGraw-Hill Companies.

[0203] As used herein, "individual" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or avian (e.g., chicken) and any other vertebrate or invertebrate. In some embodiments, the individual is a human.

[0204] In some embodiments, the individual has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the individual has been identified or diagnosed with congenital adrenal hyperplasia (CAH). In some embodiments, the individual is suspected of having CAH. In some embodiments, the individual has a clinical record indicating that the individual has CAH (and optionally, the clinical record indicates that the individual should be treated with any of the compositions provided herein). In some embodiments, the individual is a pediatric individual.

[0205] As used herein, the term "pediatric individual" refers to an individual who is less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to 2 years old); children (2 years to 12 years old); and adolescents (12 years to 21 years old (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, the pediatric individual is from birth to the first 28 days of life, from 29 days to less than 2 years old, from 2 years to less than 12 years old, or from 12 years to 21 years old (up to, but not including, the twenty-second birthday). In some embodiments, the pediatric individual is from birth to the first 28 days of life, from 29 days to less than 1 year old, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year old, from 1 year to less than 2 years old, from 2 years to less than 3 years old, from 2 years to less than 7 years old, from 3 years to less than 5 years old, from 5 years to less than 10 years old, from 6 years to less than 13 years old, from 10 years to less than 15 years old, or from 15 years to less than 22 years old.

[0206] As used herein, the term "treat" or "treatment" refers to a therapeutic or alleviating measure. Beneficial or desired clinical outcomes include, but are not limited to, completely or partially alleviating symptoms associated with a disease or disorder or condition, reducing the severity of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, improving or alleviating the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean extended survival as compared to expected survival of an untreated individual.

[0207] As used herein, the term "prevent" means preventing, in whole or in part, the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0208] The term "administration" or "administering" refers to a method of giving a vertebrate or invertebrate (including a mammal, bird, fish or amphibian) a dose of a compound or pharmaceutical preparation. Preferred methods of administration can vary depending on various factors such as the components of the pharmaceutical preparation, the site of the disease and the severity of the disease.

[0209] As used herein, a "therapeutically effective amount" is an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising a compound of formula (I), that is sufficient to achieve the desired effect and can vary depending on the nature and severity of the disease condition and the potency of the compound. A therapeutic effect is to alleviate one or more symptoms of the disease to some extent and can include curing the disease. "Curing" means eliminating the symptoms of the active disease. However, some long-term or permanent effects of the disease may still be present even after a cure has been obtained (e.g., extensive tissue damage).

[0210] The term "amorphous" means a solid in a non-crystalline state. An amorphous solid is a disordered arrangement of molecules and thus does not have a distinguishable lattice or unit cell and therefore does not have a definable long-range order. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) or other standard techniques known to those skilled in the art.

[0211] As used herein, a "time window" refers to a time period defined by a window start time and a window stop time. Both of these times refer to the local time at which the sample is collected. The phrase "the same time window" when referring to samples collected from an individual means, for example, that a sample collected at 8:15 am and a sample collected at 9:15 am are considered to be collected within the same time window, such as 2 am to 10 am or 6 am to 10 am.

[0212] Method

[0213] The present disclosure relates to a method of treating congenital adrenal hyperplasia (CAH). The method comprises administering to an individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to an individual a therapeutically effective amount of an SDD of the present disclosure, the SDD comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to an individual a therapeutically effective amount of a pharmaceutical composition of the present disclosure comprising an SDD, the SDD comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0214] The present disclosure provides methods for treating congenital adrenal hyperplasia (CAH), including administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to normalize or partially normalize the level of a biomarker associated with congenital adrenal hyperplasia. In some embodiments, normalizing or partially normalizing the level of the biomarker includes reducing the level of an elevated biomarker or increasing the level of a decreased biomarker as compared to an individual not having CAH.

[0215] The present disclosure provides methods for treating congenital adrenal hyperplasia in an individual in need thereof, the methods including administering an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof sufficient to reduce the level of one or more biomarkers associated with congenital adrenal hyperplasia. In some embodiments, the biomarker is selected from (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione in the individual.

[0216] In some embodiments, a decrease in the level of any biomarker (e.g., any one of 17-OHP, ACTH, and androstenedione) is determined by comparing the level of the biomarker measured during the rhythmic release on the day prior to administering the compound of formula (I) or a pharmaceutically acceptable salt thereof and the level of the biomarker measured during the rhythmic release on the day after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof. The day prior to administering the compound of formula (I) is applicable to an individual who has not previously administered the compound of formula (I) within at least the past 24 hours.

[0217] In some embodiments, the rhythmic release of the biomarker associated with CAH occurs between 2:00 am and 10:00 am. In other embodiments, the rhythmic release of the biomarker associated with CAH occurs between 6:00 am and 10:00 am.

[0218] In some embodiments of any of the methods disclosed herein, the compound of formula (I) or a pharmaceutically acceptable salt is administered to the individual at night or before sleep (i.e., administered before bedtime). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three to eight hours prior to the rhythmic 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 rhythmic release of the biomarker. Administration prior to the rhythmic release can be adapted for shift workers (e.g., those who work at night and sleep during the day), in which case the administration need not occur at night. Thus, the administration depends on the expected rhythmic release of the biomarker and can vary according to the specific work and sleep patterns of the individual (i.e., the individual, the patient).

[0219] In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from the pre-administration level. 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%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 55% to about 90%, or from about 60% to about 90% from the pre-administration level.

[0220] In some embodiments, the level of 17-hydroxyprogesterone is reduced to a level within the range of 17-hydroxyprogesterone expected for an individual not suffering from CAH, i.e., less than 1,000 ng / dL or less than 200 ng / dL.

[0221] In some embodiments of the methods provided herein, the level of adrenocorticotropic hormone is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from the pre-administration level. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 25%. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 40%. In some embodiments, the level of adrenocorticotropic hormone is reduced by at least 50%.

[0222] 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%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 55% to about 90%, or from about 60% to about 90% from the pre-administration level.

[0223] In some embodiments, the level of adrenocorticotropic hormone is reduced to a level within the range of adrenocorticotropic hormone expected for an individual not suffering from CAH.

[0224] 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 least 35%, at least 40%, at least 50%, at least 55%, or at least 60% from the pre - administration level. In some embodiments, the level of 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%.

[0225] In some embodiments of the methods provided herein, the level of androstenedione is reduced by an amount of from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 55% to about 90%, or from about 60% to about 90% from the pre - administration level.

[0226] In some embodiments, the level of androstenedione is reduced to a level within the range of androstenedione expected for an individual not suffering from CAH, i.e., less than 200 ng / dL.

[0227] Also provided herein are methods for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in an individual suffering from classical congenital adrenal hyperplasia, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce one or more CAH biomarkers in the individual (e.g., reducing androstenedione in the individual). Growth impairment can refer to, for example, an accelerated height velocity, an accelerated weight velocity, and / or an accelerated bone age.

[0228] Provided herein are methods for reducing the level of one or more biomarkers of congenital adrenal hyperplasia in an individual suffering from congenital adrenal hyperplasia, the method comprising administering to the individual 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.

[0229] Provided herein are methods for controlling congenital adrenal hyperplasia by reducing the dose of corticosteroid administered to an individual suffering from congenital adrenal hyperplasia, the method comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is a glucocorticoid.

[0230] The present invention also provides a method for reducing the severity of one or more side effects of glucocorticoid therapy in an individual suffering from congenital adrenal hyperplasia, said method comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof. The long-term effects of glucocorticoid therapy are well documented in the art (see, for example, 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 each biological system, such as the musculoskeletal system (e.g., osteoporosis, avascular necrosis of bone, and myopathy), the endocrine and metabolic systems (e.g., hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, adrenal suppression), the gastrointestinal system (e.g., gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis), the cardiovascular system (e.g., hypertension, coronary heart disease, ischemic heart disease, heart failure), the skin system (e.g., dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, and alopecia), the neuropsychiatric system (e.g., mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive deficits, psychosis, dementia, and delirium), the ophthalmic system (e.g., cataract, glaucoma, ptosis, mydriasis, opportunistic eye infections, and central serous chorioretinopathy), and the immune system (e.g., cell-mediated immunosuppression, increased susceptibility to infection, and reactivation of latent infections).

[0231] Thus, in some embodiments, the side effects of glucocorticoid therapy are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, 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, alopecia, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive deficits, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, increased susceptibility to infection, reactivation of latent infections, and any combination thereof.

[0232] The present invention provides a method for treating congenital adrenal hyperplasia in an individual, 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 individual;

[0233] (ii) analyzing the level of the one or more biomarkers to determine whether the level of the one or more biomarkers is elevated compared to a healthy individual without congenital adrenal hyperplasia; and

[0234] (iii) if the individual is determined to have an elevated level of the one or more biomarkers, administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the method further comprises (iv) after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof, measuring the level of the one or more biomarkers in a biological sample obtained from the individual, and determining whether the individual has a reduced level of the one or more biomarkers compared to the measurement in step (i). In some embodiments, the method further comprises (v) if the individual has a reduced level of the one or more biomarkers, continuing to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof

[0236] In some embodiments, steps (i) and (iv) are performed on biological samples collected from the individual in a similar manner and within the same time window. In some embodiments, steps (i) and (iv) are performed on biological samples collected from the individual within the time window from 2:00 am to 10:00 am. In some embodiments, steps (i) and (iv) are performed on biological samples collected from the individual within the time window from 6:00 am to 10:00 am.

[0237] In some embodiments, steps (i) and (iv) comprise measuring the level of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione.

[0238] In some embodiments, steps (i) and (iv) comprise measuring the levels of (a) 17-hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione.

[0239] 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.

[0240] 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.

[0241] In some embodiments of the methods of the present disclosure, the compound of formula (I) is administered in an amount equivalent to about 25 mg to about 150 mg of the free base of the compound of formula (I). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 50 mg or about 100 mg of the free base of the compound of formula (I).

[0242] In some embodiments of the methods disclosed herein, the compound of formula (I) is administered in free base form.

[0243] In some embodiments of the methods disclosed herein, the compound of formula (I) is administered once daily.

[0244] Also provided herein are methods of treating CAH in pediatric individuals. The methods comprise administering to the pediatric individual a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering to the pediatric individual a therapeutically effective amount of the SDD of the present disclosure, the SDD comprising a polymer and the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering to the pediatric individual a therapeutically effective amount of a pharmaceutical composition of the present disclosure comprising the SDD, the SDD comprising a polymer and the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pediatric individual is a neonate. In some embodiments, the pediatric individual is an infant. In some embodiments, the pediatric individual is a child. In some embodiments, the pediatric individual is an adolescent.

[0245] In some embodiments of the methods of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual in a fed state. As used herein, the term "fed state" means that the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered from about 1 hour before consuming food or a nutritional composition to about 1 hour after consuming food or a nutritional composition. As used herein, the term "fasted state" means an interval of at least 2 hours between consuming food or a nutritional composition and administering the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual together with food or a nutritional composition (such as a nutritional supplement or formula food, meal replacement beverage, liquid dietary supplement, or high-calorie liquid meal). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual within about 1 hour before the individual has consumed food or a nutritional composition. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual within about 1 hour after the individual has consumed food or a nutritional composition. Examples of suitable nutritional compositions include, but are not limited to, infant formula, dietary supplements, meal replacements, 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 for enteral and parenteral supplements for infants, specialty infant formulas, supplements for the elderly, and those with gastrointestinal difficulties and / or malabsorption. Adult and pediatric nutritional formulas are well known in the art and are commercially available (e.g., from Ross Products Division, Abbott Laboratories, Columbus, Ohio of and ).

[0246] In some embodiments, the nutritional composition is in liquid form. When in liquid form, the energy density of the nutritional composition can be from about 0.6 Kcal / mL to about 3 Kcal / mL. In some embodiments, the nutritional composition is in solid form or powder form. When in solid form or powder form, the nutritional supplement can contain from about 1.2 Kcal / g to greater than 9 Kcal / g, such as from about 3 Kcal / g to 7 Kcal / g.

[0247] In some embodiments, the nutritional composition is a meal replacement bar. Examples include bar, Choice bar, bar, and bar. In some embodiments, the nutritional composition is a nutritional shake or meal replacement beverage. Commercially available examples include brand's adult products (e.g., Original, Plus, Enlive, High Protein, Clear and Light), Choice Slim and In some embodiments, the nutritional composition is Plus. In some embodiments, the nutritional composition is vanilla flavored Plus. Ensure It is a high-calorie liquid dietary supplement containing 1500 calories per liter, with a caloric distribution of 14.7% protein, 32% fat and 53.3% carbohydrates.

[0248] In some embodiments of the disclosed methods, a compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with 8 fluid ounces (237 mL) of Plus is administered to an individual together. In some embodiments, Plus it's vanilla flavored.

[0249] In some embodiments of the method, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual after the nutritional composition is administered. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual before the nutritional composition is administered. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual while the nutritional composition is administered.

[0250] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual, followed by administration of a nutritional composition. In some embodiments, the nutritional composition is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 60 minutes, or within a range defined by any of the foregoing 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 foregoing 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 administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the disclosed method, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual with 8 fluid ounces (237 mL) of Plus. In some embodiments, Plus is vanilla flavored.

[0251] In some embodiments, a nutritional composition is administered to an individual, followed by administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 60 minutes, or within a range defined by any of the foregoing 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 foregoing 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 administration of the nutritional composition. In some embodiments of the disclosed method, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual with 8 fluid ounces (237 mL) of Plus. In some embodiments, Plus is vanilla flavored.

[0252] In some embodiments of the method, a food effect is observed between administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the fed state and the fasted state. As used herein, the term "food effect" refers to the AUC (curve AUC) of the active substance when a compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to an individual with food or in the fed state(0-t) and / or AUC (0-∞) area under) or C max (maximum plasma concentration or peak plasma concentration) relative to the same value when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a fasting state. The food effect (F) is calculated as follows:

[0253] F% = [(X 禁食 – X 进食 ) / X 禁食 × 100

[0254] where X 进食 and X 禁食 are the AUC (AUC (0-t) and / or AUC (0-∞) ) or C max values in the fed and fasting states, 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 an individual 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 is observed upon oral administration in a fed state compared to a fasting state.

[0255] In some embodiments of the method, the ratio of the AUC in the fed state to the AUC in the fasting state is from 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 fasting state is about 5, about 6, about 7, about 8, about 9 or about 10, or within a range defined by any of the foregoing values. In some embodiments of the method, the ratio of the AUC in the fed state to the AUC in the fasting state is from about 10 to about 20.

[0256] In some embodiments of the method, the ratio of the AUC in the fed state to the AUC in the fasting 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 fasting state is 5, 6, 7, 8, 9 or 10, or within a range defined by any of the foregoing values.

[0257] In some embodiments of the method, C maxcompared to C in the fasting state max 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, C max in the fed state compared to C max in the fasting state max is about 1.5 to about 3 times higher. In some embodiments of the method, C max in the fed state compared to C max in the fasting state max 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, C max in the fed state compared to C max in the fasting state max is about 1.5 to about 3 times higher. In some embodiments, compared to the fasting state, the average C max of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the fed state max is about 2 times higher. In some embodiments of the method, C

[0258] in the fed state compared to C

[0258] in the fasting state is about 10 to about 20.In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered to an individual with a meal. In some embodiments, the meal is a high-fat, high-calorie meal. In some embodiments, the meal is a low-fat, low-calorie meal. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof is administered within about 5 minutes after the start of the meal. In some embodiments, the meal is dinner. In some embodiments, the meal is breakfast.

[0259] In some embodiments, the fed state is accompanied by a high-fat meal. In some embodiments, the fed state is accompanied by a low-fat meal. The FDA has provided draft guidance on high-fat meals 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 the test meal definitions provided by the FDA guidance.

[0260] Table 1

[0261]

[0262] The composition of the high-fat meal provided by the FDA guidance is described in Table 2.

[0263] Table 2. Composition of High-Fat Meal*

[0264]

[0265] *50% of the calories are from fat. The meal can be substituted if the content, volume, and viscosity are maintained.

[0266] The composition of the low-fat meal provided by the FDA guidance is described in Table 3.

[0267] Table 3. Composition of the low-fat meal

[0268]

[0269] *This low-fat breakfast contains 387 calories and 10 grams of fat.

[0270] In some embodiments, the high-fat meal contains 800 - 1000 total Kcal and 500 - 600 fat Kcal. In some embodiments, the low-fat meal contains 400 - 500 total Kcal and 100 - 125 fat Kcal.

[0271] Also provided herein are methods of improving gastrointestinal absorption of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an individual. The methods include orally administering to the individual a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof that is not formulated as a spray-dried dispersion. In some embodiments, the individual is a pediatric individual.

[0272] Also provided herein are methods of improving oral bioavailability of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an individual. The methods include orally administering to the individual a pharmaceutical composition of the present disclosure, wherein the improvement is relative to oral administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof that is not formulated as a spray-dried dispersion.

[0273] In some embodiments of the methods provided herein, the individual is a pediatric individual.

[0274] Also provided herein are methods of treating congenital adrenal hyperplasia (CAH) in an individual in need thereof, including administering to the individual a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a lipid semi-solid formulation. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is administered to an individual in a fed state.

[0275] Also provided herein is a pharmaceutical composition of the present disclosure for use in a method of treating congenital adrenal hyperplasia (CAH) in an individual. In some embodiments, the individual is in a fed state.

[0276] In some embodiments, the pharmaceutical composition is administered to an individual together with a nutritional composition. In some embodiments, the nutritional composition is a liquid dietary supplement containing from about 1000 to about 2000 calories per liter and having a fat content greater than about 30%. In some embodiments, the nutritional composition is a liquid dietary supplement containing 1500 calories per liter, with a calorie distribution of 14.7% protein, 32% fat, and 53.3% carbohydrates. In some embodiments, the nutritional composition is administered in an amount of from about 6 to about 12 fluid ounces. In some embodiments, the nutritional composition is administered in an amount of about 8 fluid ounces. In some embodiments, the nutritional composition is administered within 30 minutes of administering the pharmaceutical composition.

[0277] In some embodiments, the pharmaceutical composition exhibits a positive food effect. In some embodiments, when comparing the oral administration of the pharmaceutical composition in the fed state and the fasted state, a positive food effect is measured in terms of C max , AUC, or a combination thereof. In some embodiments, the ratio of the AUC of the compound of formula (I) in the fed state to the AUC of the compound of formula (I) in the fasted state is from about 5 to about 10. In some embodiments, 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 from 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 from about 10 to about 20. In some embodiments, 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 from 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 from about 1 to about 4 or from about 5 to about 10. In some embodiments, 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 from about 1 to about 4 or from 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 from about 1 to about 4. In some embodiments, 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 from 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 from about 1.5 to about 3. In some embodiments, the Cmax The ratio of C of the compound of formula (I) in the fed state max to that 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, C of the compound of formula (I) in the fed state max to C of the compound of formula (I) in the fasted state max 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, C of the compound of formula (I) in the fed state max to C of the compound of formula (I) in the fasted state max 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, C of the compound of formula (I) in the fed state max to C of the compound of formula (I) in the fasted state max is 1.5 to 3.

[0278] In some embodiments, the individual is a pediatric individual.

[0279] In some embodiments, the pharmaceutical composition is formulated for oral administration and exhibits a positive food effect when orally administered. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 5 to about 10. In some embodiments, the compound of formula (I) has a ratio of C in the fed state max to C in the fasted state max . In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 10 to about 20. In some embodiments, the compound of formula (I) has a ratio of C in the fed state max to C in the fasted state max . In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasted state of about 1 to about 4 or about 5 to about 10. In some embodiments, the compound of formula (I) has a ratio of C in the fed state max to C in the fasted state maxratio. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasting state of from about 1 to about 4. In some embodiments, the compound of formula (I) has a C max in the fed state to C max in the fasting state. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasting state of from about 1.5 to about 3. In some embodiments, the compound of formula (I) has a C max in the fed state to C max in the fasting state. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasting state of 1 to 4 or 5 to 10. In some embodiments, the compound of formula (I) has a C max in the fed state to C max in the fasting state. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasting state of 1 to 4. In some embodiments, the compound of formula (I) has a C max in the fed state to C max in the fasting state. In some embodiments, the compound of formula (I) has a ratio of AUC in the fed state to AUC in the fasting state of 1.5 to 3. In some embodiments, the compound of formula (I) has a C max in the fed state to C max in the fasting state.

[0280] In some embodiments, the pharmaceutical composition is administered to an individual 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 dinner. In some embodiments, the meal is breakfast.

[0281] In some embodiments, administration of the pharmaceutical composition exhibits a positive food effect. In some embodiments, when comparing oral administration of the pharmaceutical composition in the fed state and the fasting state, a positive food effect is measured in terms of C max , AUC or a combination thereof of the compound of formula (I). In some embodiments, the ratio of AUC of the compound of formula (I) in the fed state to AUC of the compound of formula (I) in the fasting state is from about 5 to about 10. In some embodiments, C max of the compound of formula (I) in the fed state to C maxThe ratio 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 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 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 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 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 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 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 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.

[0282] For the avoidance of doubt, also provided herein are the corresponding compounds of formula (I) or pharmaceutically acceptable salts thereof, or the corresponding pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof, for use in the corresponding methods described herein.

[0283] For the avoidance of doubt, also provided herein is the use of a corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a corresponding method as described herein.

[0284] For the avoidance of doubt, also provided herein is the use of a corresponding pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the corresponding methods described herein.

[0285] Reduction of glucocorticoid load, adrenal androgens and precursors

[0286] Glucocorticoid is a class of corticosteroids, which is a class of steroid hormones. Glucocorticoid is a corticosteroid combined with a glucocorticoid receptor, which is present in almost every vertebrate cell. In some embodiments, the individual receives a glucocorticoid dosage simultaneously. 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.

[0287] In some embodiments, glucocorticoid dosage is measured with hydrocortisone equivalent.In some embodiments, glucocorticoid dosage is measured as multiple of the upper limit of normal value of physiological dose with hydrocortisone equivalent.Any glucocorticoid can be given with the dosage that provides to produce the roughly the same glucocorticoid effect with normal cortisol; Described dosage is called physiological dose, replacement dose or maintenance dose.

[0288] In some embodiments, the glucocorticoid dose is a physiological dose measured after a period of time of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose is about 4 mg / m2 measured after a period of time of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 / day to about 12 mg / m 2 In some embodiments, the glucocorticoid dose is about 4 mg / m measured after a period of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 2 / day to about 9 mg / m 2physiological dose per day. In some embodiments, the glucocorticoid dose is less than about 8 mg / m 2 physiological dose per day.

[0289] In some embodiments, the glucocorticoid dose is the physiological dose measured after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time. In some embodiments, the glucocorticoid dose is about 4 mg / m 2 per day to about 12 mg / m 2 physiological dose per day. In some embodiments, the glucocorticoid dose is about 4 mg / m 2 per day to about 9 mg / m 2 physiological dose per day. In some embodiments, the glucocorticoid dose is less than about 8 mg / m 2 physiological dose per day.

[0290] In some embodiments, the glucocorticoid dose administered to an individual concurrently is the normal physiological dose of hydrocortisone equivalent. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose administered to an individual concurrently is determined. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose administered to an individual concurrently is determined. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 2 mg / m 2 per day to about 16 mg / m 2 per day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 4 mg / m 2 per day to about 12 mg / m 2 per day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 5 mg / m 2 per day to about 11 mg / m 2 per day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 6 mg / m 2 per day to about 10 mg / m 2 per day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 7 mg / m 2 per day to about 9 mg / m 2 / day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 4 mg / m 2 / day to about 9 mg / m 2 / day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 8 mg / m 2 / day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is about 12 mg / m 2 / day. In some embodiments, the normal physiological dose of hydrocortisone equivalent is less than about 8 mg / m 2 / day. In some embodiments, the normal physiological dose of hydrocortisone equivalent 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 the range defined by any of the foregoing values.

[0291] In some embodiments, the glucocorticoid dose administered to an individual concurrently is the upper limit of the normal value of the normal physiological dose of hydrocortisone equivalent. In some embodiments, the glucocorticoid dose administered to an individual concurrently is determined after a period of time following administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid dose administered to an individual concurrently is determined after a period of time following administration of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the upper limit of the normal value is 1.5 times the normal physiological dose. In some embodiments, the upper limit of the normal value is about 1.5 times the normal physiological dose. In some embodiments, the upper limit of the normal value is about 1.5 times the normal physiological dose. In some embodiments, the upper limit of the normal value is about 2 times the normal physiological dose. In some embodiments, the upper limit of the normal value is about 2.5 times the normal physiological dose. In some embodiments, the upper limit of the normal value 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 the range defined by any of the foregoing values.

[0292] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 10%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 20%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 30%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 40%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 60%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 70%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by less than about 20%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 20% to about 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by more than about 50%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 10%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 20%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 30%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 40%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 50%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 60%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 70%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by less than about 20%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by about 20% to about 50%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucocorticoid dose of an individual is reduced by more than about 50%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the glucocorticoid dose of an individual is reduced within the range defined by any of the foregoing values.

[0295] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is reduced by at least 25%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is reduced by at least 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is less than 1.5 times the upper limit of the normal value. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is within the normal limits.

[0296] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17 - hydroxyprogesterone is reduced by at least about 25%, wherein the reduction in the level of 17 - hydroxyprogesterone is relative to the level of 17 - hydroxyprogesterone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17 - hydroxyprogesterone is reduced by at least about 50%, wherein the reduction in the level of 17 - hydroxyprogesterone is relative to the level of 17 - hydroxyprogesterone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17 - hydroxyprogesterone is less than about 1.5 times the upper limit of normal values. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17 - hydroxyprogesterone is within normal limits.

[0297] In some embodiments, the level of 17 - hydroxyprogesterone in an individual is reduced within the range defined by any of the foregoing values.

[0298] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least 25%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least 40%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is less than 1.5 times the upper limit of normal values. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is within normal limits.

[0299] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 25%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 40%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 50%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is less than about 1.5 times the upper limit of normal. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of adrenocorticotropic hormone is within normal limits.

[0300] In some embodiments, the level of adrenocorticotropic hormone in an individual is reduced within the range defined by any of the foregoing values.

[0301] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least 25%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least 30%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is less than 1.5 times the upper limit of normal. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is within normal limits.

[0302] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least about 25%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least about 30%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is reduced by at least about 50%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is less than about 1.5 times the upper limit of normal. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of androstenedione is within the normal limits.

[0303] In some embodiments, the level of androstenedione in an individual is reduced within the range defined by any of the foregoing values.

[0304] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least 25%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least 30%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least 50%, wherein the reduction in 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, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is less than 1.5 times the upper limit of normal. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is within the normal limits.

[0305] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least about 25%, wherein the reduction in the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least about 30%, wherein the reduction in the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is reduced by at least about 50%, wherein the reduction in the level of testosterone is relative to the level of testosterone prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is less than about 1.5 times the upper limit of normal values. In some embodiments, after administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is within normal limits.

[0306] In some embodiments, the level of testosterone in the individual is reduced within the range defined by any of the foregoing values.

[0307] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is reduced by at least 50% and the level of androstenedione is reduced by at least 50%, wherein the reduction in the levels of 17-hydroxyprogesterone and androstenedione is relative to the levels of 17-hydroxyprogesterone and androstenedione prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is less than 1.5 times the upper limit of normal values and the level of androstenedione is less than about 1.5 times the upper limit of normal values. In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits.

[0308] In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is reduced by at least about 50% and the level of androstenedione is reduced by at least about 50%, wherein the reduction in 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 composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is less than 1.5 times the upper limit of normal and the level of androstenedione is less than about 1.5 times the upper limit of normal. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits.

[0309] In some embodiments, the levels of 17-hydroxyprogesterone and androstenedione in an individual are reduced within the range defined by any of the foregoing values.

[0310] In some embodiments, an individual exhibits a reduction in glucocorticoid load after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the reduction in glucocorticoid load is relative to the glucocorticoid load prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility are improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, wherein the improvement in the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, an individual exhibits a reduction in glucocorticoid burden after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, wherein the reduction in glucocorticoid burden is relative to the glucocorticoid burden prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, one or more symptoms of glucocorticoid burden selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumors, and fertility are improved, wherein the improvement of the one or more symptoms is relative to the state of the one or more symptoms prior to administration of the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the quality of life measured by EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) in an individual is improved, wherein the improvement in 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.

[0313] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the fatigue of an individual is alleviated, wherein the alleviation of fatigue is relative to the fatigue prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the sleep of an individual increases, 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.

[0315] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the insulin resistance of an individual is reduced, wherein the reduction in insulin resistance is relative to the insulin resistance prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucose tolerance of an individual is reduced, 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.

[0317] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the glucose control of an individual is increased, 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.

[0318] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the blood lipid levels reflecting dyslipidemia in an individual are reduced, wherein the reduction in blood lipid levels is relative to the blood lipid levels prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the blood lipid levels reflecting hyperlipidemia in an individual are reduced, wherein the reduction in blood lipid levels is relative to the blood lipid levels prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the bone mineral density of an individual is increased, 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.

[0321] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the bone turnover of an individual is increased, 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.

[0322] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the fat mass of an individual is reduced, wherein the reduction in fat mass is relative to the fat mass prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the body weight of an individual is reduced, wherein the reduction in body weight is relative to the body weight prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, central obesity of an individual is reduced, wherein the reduction in central obesity is relative to the central obesity prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the blood pressure of an individual increases, 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.

[0326] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the severity of hirsutism in an individual is reduced, wherein the reduction in the severity of hirsutism is relative to the severity of hirsutism prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the menstrual cyclicity of an individual increases, 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.

[0328] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the control of testicular adrenal rest tumors in an individual increases, wherein the increase in the control of testicular adrenal rest tumors is relative to the control of testicular adrenal rest tumors prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the fertility of an individual increases, 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.

[0330] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the gonadotropin level in an individual increases, wherein the increase in the gonadotropin level is relative to the gonadotropin level prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the progesterone level in an individual increases, wherein the increase in the progesterone level is relative to the progesterone level prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments, after a period of time following administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the sperm level of an individual increases, wherein the increase in sperm level is relative to the sperm level prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, after a period of time following administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the LH (luteinizing hormone) level of an individual increases, wherein the increase in LH level is relative to the LH level prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the period of administration is at least about 4 weeks. In some embodiments, the period of administration is at least about 24 weeks. In some embodiments, the period of administration is at least about one year. In some embodiments, the period of administration is at least 4 weeks. In some embodiments, the period of administration is at least 24 weeks. In some embodiments, the period of administration is at least one year. In some embodiments, the period of administration is less than about 1 day. In some embodiments, the period of administration is about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or within the range of any of the foregoing values. In some embodiments, the period of administration is about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or within the range of any of the foregoing values. In some embodiments, the period of administration is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or within the range of any of the foregoing values. It is understood that comparative measurements are preferably taken in the morning.

[0335] In some embodiments, the individual is a pediatric individual. In some embodiments, the pediatric individual is less than or equal to six years old. In some embodiments, the pediatric individual is greater than six years old and less than eleven years old. In some embodiments, the pediatric individual is greater than ten years old and less than fifteen years old. In some embodiments, the pediatric individual is greater than fourteen years old and less than nineteen years old.

[0336] In some embodiments, the individual is an adult individual. In some embodiments, the individual is over eighteen years old. In some embodiments, the individual is female. In some embodiments, the individual is male.

[0337] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition as described herein. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as the pharmaceutical composition described in Example 9. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as the pharmaceutical composition described in Example 11. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as the pharmaceutical composition described in Example 12. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as the pharmaceutical composition described in Example 13. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a hydrochloride salt or a p-toluenesulfonate salt.

[0338] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a p-toluenesulfonate salt as described herein.

[0339] For the avoidance of doubt, there are also provided herein the corresponding compounds of formula (I) or pharmaceutically acceptable salts thereof for the corresponding methods described herein, or the corresponding pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0340] For the avoidance of doubt, there is also provided herein the use of the corresponding compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the corresponding method described herein.

[0341] For the avoidance of doubt, there is also provided herein the 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 the corresponding method described herein.

[0342] p-Toluenesulfonate salt

[0343] 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-toluenesulfonate.

[0344] In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine p-toluenesulfonate is a crystalline salt. In some embodiments, the p-toluenesulfonic acid crystalline salt has Form 1.

[0345] In some embodiments, the p-toluenesulfonic acid crystalline salt has substantially as Figure 27The X-ray powder diffraction pattern shown in Figure 28 The DSC thermogram shown in Figure 28 The thermogravimetric analysis (TGA) thermogram shown in

[0346] In some embodiments, the crystalline tosylate salt has at least one X-ray powder diffraction (XRPD) peak at 2θ (±0.2 degrees) selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees. In some embodiments, the crystalline tosylate salt has at least two X-ray powder diffraction (XRPD) peaks at 2θ (±0.2 degrees) selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees. In some embodiments, the crystalline tosylate salt has at least three X-ray powder diffraction (XRPD) peaks at 2θ (±0.2 degrees) selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees. In some embodiments, the crystalline tosylate salt has at least four X-ray powder diffraction (XRPD) peaks at 2θ (±0.2 degrees) selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees. In some embodiments, the crystalline tosylate salt has characteristic X-ray powder diffraction (XRPD) peaks at 2θ (±0.2 degrees) selected from 9.1, 11.3, 13.2, 16.3, and 21.1 degrees. In some embodiments, the crystalline tosylate salt has an endothermic peak with a melting onset at about 156 °C (22.2 J / g) in a differential scanning calorimetry (DSC) thermogram.

[0347] Lipid semi-solid preparation

[0348] Provided herein is a lipid semi-solid preparation that is a pharmaceutical composition, comprising:

[0349] (a) A compound of formula (I):

[0350]

[0351] or a pharmaceutically acceptable salt thereof; and

[0352] (b) One or more of an oil phase medium, an emulsifier, a nonionic surfactant, and a solubilizer.

[0353] In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises from about 1 wt% to about 20 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises from about 5 wt% to about 15 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises about 10 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt% or 20 wt%, or a compound of formula (I) or a pharmaceutically acceptable salt thereof within the range of any of the foregoing values.

[0354] In some embodiments, the pharmaceutical composition comprises an oil phase vehicle. The oil phase vehicle is a solvent with poor miscibility with water. In some embodiments, the pharmaceutical composition comprises from about 1 wt% to about 50 wt% of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises from about 20 wt% to about 50 wt% of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises from about 35 wt% to about 45 wt% of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 39 wt% of the oil phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt% or 45 wt%, or an oil phase vehicle within the range of any of the foregoing values.

[0355] In some embodiments, the oil phase vehicle is selected from medium-chain triglycerides, glycerol, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and diethylene glycol monoethyl ether. In some embodiments, the oil 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.

[0356] In some embodiments, the pharmaceutical composition comprises an emulsifier. An emulsifier is a compound or substance that serves as a stabilizer for an emulsion. In some embodiments, the pharmaceutical composition comprises from about 5 wt% to about 50 wt% of an emulsifier. In some embodiments, the pharmaceutical composition comprises from about 10 wt% to about 30 wt% of an emulsifier. In some embodiments, the pharmaceutical composition comprises from about 15 wt% to about 25 wt% of an emulsifier. In some embodiments, the pharmaceutical composition comprises about 20 wt% of an emulsifier. In some embodiments, the pharmaceutical composition comprises about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt%, or an emulsifier within the range of any of the foregoing values.

[0357] In some embodiments, the emulsifier is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and diethylene glycol monoethyl ether. In some embodiments, the emulsifier is propylene glycol dicaprylate / dicaprate. In some embodiments, propylene glycol dicaprylate / dicaprate is Labrafac TMPG.

[0358] In some embodiments, the pharmaceutical composition comprises a nonionic surfactant. A nonionic surfactant is a substance having a hydrophilic head and a hydrophobic tail and does not have a charge added as a formulation component to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition comprises from about 5 wt% to about 50 wt% of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises from about 10 wt% to about 30 wt% of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises from about 15 wt% to about 25 wt% of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 19 wt% of a nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt%, or a nonionic surfactant within the range of any of the foregoing values.

[0359] In some embodiments, the nonionic surfactant is selected from glyceryl oleoyl polyoxyl 6, glyceryl linoleoyl polyoxyl 6, polysorbate 80, polysorbate 20, polyethylene glycol glyceryl laurate, glyceryl lauroyl polyoxyl 32, poloxamer, PEG-32 stearate, and PEG-32 hydrogenated palm glyceride. In some embodiments, the nonionic surfactant is glyceryl lauroyl polyoxyl 32. In some embodiments, glyceryl lauroyl polyoxyl 32 is 44 / 14.

[0360] In some embodiments, the pharmaceutical composition comprises a solubilizer. The solubilizer is a solvent that aids in solubilizing the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises from about 1 wt% to about 50 wt% of the solubilizer. In some embodiments, the pharmaceutical composition comprises from about 1 wt% to about 20 wt% of the solubilizer. In some embodiments, the pharmaceutical composition comprises from about 5 wt% to about 15 wt% of the solubilizer. In some embodiments, the pharmaceutical composition comprises about 11 wt% of the solubilizer. In some embodiments, the pharmaceutical composition comprises about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt% or 20 wt%, or a solubilizer within the range of any of the foregoing values.

[0361] In some embodiments, the solubilizer is selected from glyceryl oleoyl polyoxyl 6, glyceryl linoleoyl polyoxyl 6, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, polyethylene glycol glyceryl laurate, glyceryl lauroyl polyoxyl 32, and poloxamer. In some embodiments, the solubilizer is vitamin E polyethylene glycol succinate. In some embodiments, vitamin E polyethylene glycol succinate is TPGS. In some embodiments, vitamin E polyethylene glycol succinate is vitamin E / TPGS 260.

[0362] In some embodiments, the pharmaceutical composition comprises:

[0363] (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;

[0364] (b) an oil phase vehicle;

[0365] (c) an emulsifier;

[0366] (d) A nonionic surfactant; and

[0367] (e) A solubilizer.

[0368] In some embodiments, the pharmaceutical composition comprises:

[0369] (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;

[0370] (b) About 35 wt% to about 45 wt% of an oil phase vehicle;

[0371] (c) About 15 wt% to about 25 wt% of an emulsifier;

[0372] (d) About 15 wt% to about 25 wt% of a nonionic surfactant; and

[0373] (e) About 5 wt% to about 15 wt% of a solubilizer.

[0374] In some embodiments, the pharmaceutical composition comprises:

[0375] (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;

[0376] (b) About 39 wt% of an oil phase vehicle;

[0377] (c) About 20 wt% of an emulsifier;

[0378] (d) About 19 wt% of a nonionic surfactant; and

[0379] (e) About 11 wt% of a solubilizer.

[0380] In some embodiments, the pharmaceutical composition comprises:

[0381] (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;

[0382] (b) A medium-chain triglyceride component;

[0383] (c) Propylene glycol dicaprylate / dicaprate component;

[0384] (d) Lauroyl polyoxyl-32 glyceride component; and

[0385] (e) Vitamin E polyethylene glycol succinate component.

[0386] In some embodiments, the pharmaceutical composition comprises:

[0387] (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;

[0388] (b) About 35 wt% to about 45 wt% of medium-chain triglycerides;

[0389] (c) About 15 wt% to about 25 wt% of propylene glycol dicaprylate / dicaprate;

[0390] (d) About 15 wt% to about 25 wt% of lauroyl polyoxyl-32 glyceride; and

[0391] (e) About 5 wt% to about 15 wt% of vitamin E polyethylene glycol succinate.

[0392] In some embodiments, the pharmaceutical composition comprises:

[0393] (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;

[0394] (b) About 39 wt% of medium-chain triglycerides;

[0395] (c) About 20 wt% of propylene glycol dicaprylate / dicaprate;

[0396] (d) About 19 wt% of lauroyl polyoxyl-32 glyceride; and

[0397] (e) About 11 wt% of vitamin E polyethylene glycol succinate.

[0398] In some embodiments, the lipid semi-solid pharmaceutical composition has a viscosity of about 15 centipoise to about 40 centipoise at about 45 °C. In some embodiments, the lipid semi-solid pharmaceutical composition has a viscosity of about 26 centipoise to about 30 centipoise at about 45 °C. In some embodiments, the lipid semi-solid pharmaceutical composition has a viscosity of about 5 centipoise to about 25 centipoise at about 60 °C. In some embodiments, the lipid semi-solid pharmaceutical composition has a viscosity of about 14 centipoise to about 18 centipoise at about 60 °C.

[0399] In some embodiments, the pharmaceutical composition does not contain a combination of mannitol, croscarmellose sodium, corn starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0400] In some embodiments, the pharmaceutical composition does not contain at least one of mannitol, croscarmellose sodium, corn starch, hydroxypropyl methylcellulose, and magnesium stearate.

[0401] In some embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an amorphous form of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a free base form of the compound of formula (I). In some embodiments, the crystalline form of the compound of formula (I) has Form I.

[0402] In some embodiments, the pharmaceutical composition is formulated into a unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg 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 an amount of about 75 mg to about 150 mg in the unit dosage form 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 an amount of about 50 mg in the unit dosage form 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 an amount of about 100 mg in the unit dosage form 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 an amount of about 25 mg in the unit dosage form based on the weight of the free base.

[0403] In some embodiments, the pharmaceutical composition is in the form of a tablet, capsule, sachet, powder, granule, coated granule, coated tablet, enteric-coated tablet, enteric-coated capsule, melt bar, or melt film. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the dosage form is coated.

[0404] Some embodiments provide a method for preparing a pharmaceutical composition, comprising:

[0405] (a) Mix a mixture of a heating oil phase medium, an emulsifier, a nonionic surfactant, and a solubilizer;

[0406] (b) Mix the mixture of step (a) until a homogeneous mixture is obtained; and

[0407] (c) Mix 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 to form a composition.

[0408] In some embodiments, the method further comprises:

[0409] (d) Encapsulate the composition of step (c) within a capsule shell to form a capsule; and

[0410] (e) Seal the capsule of step (d) in a mixture of a sealing agent and a sealing solvent.

[0411] Liquid preparation

[0412] The present disclosure provides a pharmaceutical composition in an oral solution dosage form, comprising:

[0413] (a) A compound of formula (I):

[0414]

[0415] or a pharmaceutically acceptable salt thereof;

[0416] (b) One or more of a sweetening agent, an antioxidant, and a flavoring agent; and

[0417] (c) A liquid medium.

[0418] In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises from about 1 w / v% to about 50 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises from about 1 w / v% to about 10 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises about 5 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, based on the weight of the free base, the pharmaceutical composition comprises about 1 w / v%, 2 w / v%, 3 w / v%, 4 w / v%, 5 w / v%, 6 w / v%, 7 w / v%, 8 w / v%, 9 w / v% or 10 w / v%, or a compound of formula (I) or a pharmaceutically acceptable salt thereof within the range of any of the foregoing values.

[0419] In some embodiments, the pharmaceutical composition comprises a sweetening agent. A sweetening agent is a formulation component added to improve the taste. In some embodiments, the pharmaceutical composition comprises from about 0.01 w / v% to about 1.5 w / v% of the sweetening agent. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / v% to about 0.5 w / v% of the sweetening agent. In some embodiments, the pharmaceutical composition comprises about 0.15 w / v% of the sweetening agent. In some embodiments, the pharmaceutical composition comprises about 0.1 w / v%, 0.2 w / v%, 0.3 w / v%, 0.4 w / v% or 0.5 w / v%, or a sweetening agent within the range of any of the foregoing values.

[0420] In some embodiments, the sweetening agent is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame. In some embodiments, the sweetening agent is saccharin.

[0421] In some embodiments, the pharmaceutical composition comprises an antioxidant. An antioxidant is a formulation component included to improve stability by preventing oxidation. In some embodiments, the pharmaceutical composition comprises from about 0.01 w / v% to about 1.5 w / v% of the antioxidant. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / v% to about 0.5 w / v% of the antioxidant. In some embodiments, the pharmaceutical composition comprises about 0.17 w / v% of the antioxidant. In some embodiments, the pharmaceutical composition comprises about 0.1 w / v%, 0.2 w / v%, 0.3 w / v%, 0.4 w / v% or 0.5 w / v%, or an antioxidant within the range of any of the foregoing values.

[0422] In some embodiments, the antioxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone, and citric acid. In some embodiments, the antioxidant is butylated hydroxytoluene.

[0423] In some embodiments, the pharmaceutical composition comprises a flavoring agent. A flavoring agent is a formulation component added to mask the taste through fragrance. In some embodiments, the pharmaceutical composition comprises from about 0.01 w / v% to about 0.5 w / v% of the flavoring agent. In some embodiments, the pharmaceutical composition comprises from about 0.05 w / v% to about 0.2 w / v% of the flavoring agent. In some embodiments, the pharmaceutical composition comprises about 0.10 w / v% of the flavoring agent. In some embodiments, the pharmaceutical composition comprises about 0.05 w / v%, 0.06 w / v%, 0.07 w / v%, 0.08 w / v%, 0.09 w / v%, 0.10 w / v%, 0.11 w / v%, 0.12 w / v%, 0.13 w / v%, 0.14 w / v%, 0.15 w / v%, 0.16 w / v%, 0.17 w / v%, 0.18 w / v%, 0.19 w / v% or 0.2 w / v%, or a flavoring agent within the range of any of the foregoing values.

[0424] In some embodiments, the flavoring agent is selected from FONA Orange Flavor, FONA Fruit Flavor, FONA Grape Flavor, Firmenich SA Lemon Flavor, Firmenich Tetrarome Orange Flavor, IFF Cherry Flavor, and IFF Grape Flavor. In some embodiments, the flavoring agent is FONA Orange Flavor.

[0425] The liquid vehicle is a solvent capable of dissolving or partially dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof for the purpose of delivering as an oral administration solution. In some embodiments, the pharmaceutical composition comprises from about 50 w / v% to about 99.9 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises from about 90 w / v% to about 99 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises from 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 w / v%, 91 w / v%, 92 w / v%, 93 w / v%, 94 w / v%, 95 w / v%, 96 w / v%, 97 w / v%, 98 w / v% or 99 w / v%, or a liquid vehicle within the range of any of the foregoing values.

[0426] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerol, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and diethylene glycol monoethyl ether. In some embodiments, the liquid vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides are Labrafac Lipophile WL1349.

[0427] 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 from about 1 w / v% to about 50 w / v% of a surfactant. In some embodiments, the pharmaceutical composition comprises from about 10 w / v% to about 30 w / v% of a surfactant. In some embodiments, the pharmaceutical composition comprises about 20 w / v% of a surfactant. In some embodiments, the pharmaceutical composition comprises about 10 w / v%, 11 w / v%, 12 w / v%, 13 w / v%, 14 w / v%, 15 w / v%, 16 w / v%, 17 w / v%, 18 w / v%, 19 w / v%, 20 w / v%, 21 w / v%, 22 w / v%, 23 w / v%, 24 w / v%, 25 w / v%, 26 w / v%, 27 w / v%, 28 w / v%, 29 w / v% or 30 w / v%, or a surfactant within the range of any of the foregoing values.

[0428] In some embodiments, the surfactant is selected from oleoyl polyoxyglycerol-6, linoleoyl polyoxyglycerol-6, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, lauric acid polyethylene glycol glycerol ester, lauroyl polyoxyglycerol-32, sodium lauryl sulfate, poloxamer, corn oil PEG-6 ester, and hydrogenated palm / palm kernel oil PEG-6 ester. In some embodiments, the surfactant is oleoyl polyoxyglycerol-6. In some embodiments, oleoyl polyoxyglycerol-6 is LABRAFIL M 1944CS.

[0429] In some embodiments, the pharmaceutical composition comprises from about 50 w / v% to about 90 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition comprises from about 70 w / v% to about 80 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 75 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 74.6 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 70 w / v%, 71 w / v%, 72 w / v%, 73 w / v%, 74 w / v%, 75 w / v%, 76 w / v%, 77 w / v%, 78 w / v%, 79 w / v% or 80 w / v%, or a liquid vehicle within the range of any of the foregoing values.

[0430] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerol, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and diethylene glycol monoethyl ether. In some embodiments, the liquid vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides are Labrafac Lipophile WL1349.

[0431] In some embodiments, the pharmaceutical composition comprises:

[0432] (a) 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof;

[0433] (b) A sweetening agent;

[0434] (c) An antioxidant;

[0435] (d) A flavoring agent; and

[0436] (e) A liquid vehicle.

[0437] In some embodiments, the pharmaceutical composition further comprises a surfactant.

[0438] In some embodiments, the pharmaceutical composition comprises:

[0439] (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-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base;

[0440] (b) About 0.1 w / v% to about 0.2 w / v% of a sweetening agent;

[0441] (c) About 0.1 w / v% to about 0.2 w / v% of an antioxidant;

[0442] (d) About 0.05 w / v% to about 0.2 w / v% of a flavoring agent; and

[0443] (e) About 92 w / v% to about 97 w / v% of a liquid vehicle.

[0444] In some embodiments, the pharmaceutical composition comprises:

[0445] (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-yn-1-yl-1,3-thiazol-2-amine or a pharmaceutically acceptable salt thereof, based on the weight of the free base;

[0446] (b) About 0.15 w / v% of a sweetening agent;

[0447] (c) About 0.17 w / v% of an antioxidant;

[0448] (d) About 0.1 w / v% flavoring agent; and

[0449] (e) About 94.6 w / v% liquid vehicle.

[0450] In some embodiments, the pharmaceutical composition comprises:

[0451] (a) Based on the weight of the free base, 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;

[0452] (b) About 0.1 w / v% to about 0.2 w / v% sweetening agent;

[0453] (c) About 0.1 w / v% to about 0.2 w / v% antioxidant;

[0454] (d) About 0.05 w / v% to about 0.2 w / v% flavoring agent;

[0455] (e) About 15 w / v% to about 25 w / v% surfactant; and

[0456] (f) About 70 w / v% to about 80 w / v% liquid vehicle.

[0457] In some embodiments, the pharmaceutical composition comprises:

[0458] (a) Based on the weight of the free base, 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;

[0459] (b) About 0.15 w / v% sweetening agent;

[0460] (c) About 0.17 w / v% antioxidant;

[0461] (d) About 0.1 w / v% flavoring agent;

[0462] (e) About 20 w / v% surfactant; and

[0463] (f) About 75 w / v% liquid vehicle.

[0464] In some embodiments, the pharmaceutical composition comprises:

[0465] (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;

[0466] (b) Saccharin;

[0467] (c) Butylated hydroxytoluene;

[0468] (d) FONA orange flavoring agent; and

[0469] (e) Medium-chain triglycerides.

[0470] In some embodiments, the pharmaceutical composition further comprises polyoxy-6-glycerol oleate.

[0471] In some embodiments, the pharmaceutical composition comprises:

[0472] (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;

[0473] (b) About 0.1 w / v% to about 0.2 w / v% of saccharin;

[0474] (c) About 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene;

[0475] (d) About 0.05 w / v% to about 0.2 w / v% of FONA orange flavoring agent; and

[0476] (e) About 92 w / v% to about 97 w / v% of medium-chain triglycerides.

[0477] In some embodiments, the pharmaceutical composition comprises:

[0478] (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;

[0479] (b) About 0.15 w / v% of saccharin;

[0480] (c) About 0.17 w / v% of butylated hydroxytoluene;

[0481] (d) About 0.1 w / v% of FONA orange flavoring agent; and

[0482] (e) About 94.6 w / v% of medium-chain triglycerides.

[0483] In some embodiments, the pharmaceutical composition comprises:

[0484] (a) Based on the weight of the free base, 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;

[0485] (b) About 0.1 w / v% to about 0.2 w / v% of saccharin;

[0486] (c) About 0.1 w / v% to about 0.2 w / v% of butylated hydroxytoluene;

[0487] (d) About 0.05 w / v% to about 0.2 w / v% of FONA orange flavoring agent;

[0488] (e) About 15 wt% to about 25 wt% of oleoyl polyoxy-6 glycerides; and

[0489] (f) About 70 w / v% to about 80 w / v% of medium-chain triglycerides.

[0490] In some embodiments, the pharmaceutical composition comprises:

[0491] (a) Based on the weight of the free base, 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;

[0492] (b) About 0.15 w / v% of saccharin;

[0493] (c) About 0.17 w / v% of butylated hydroxytoluene;

[0494] (d) About 0.1 w / v% of FONA orange flavoring agent;

[0495] (e) About 20 w / v% of oleoyl polyoxy-6 glycerides; and

[0496] (f) About 75 w / v% of medium-chain triglycerides.

[0497] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) as the free base.

[0498] In some embodiments, the pharmaceutical composition is formulated into a unit dosage form, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg / mL to about 200 mg / mL, 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 an amount of about 75 mg / mL to about 150 mg / mL in the unit dosage form, 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 an amount of about 50 mg / mL in the unit dosage form, 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 an amount of about 100 mg / mL in the unit dosage form, based on the weight of the free base.

[0499] In some embodiments, the liquid pharmaceutical composition has a viscosity of about 1 centipoise to about 50 centipoise at about 25 °C.

[0500] Some embodiments provide a method for preparing a pharmaceutical composition, comprising:

[0501] (a) mixing a liquid vehicle with a sweetening agent;

[0502] (b) mixing the mixture of step (a) with an antioxidant and a flavoring agent;

[0503] (c) mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with the mixture of step (b); and

[0504] (d) mixing the mixture of step (c) with a further portion of the liquid vehicle.

[0505] In some embodiments, step (a) of the method comprises mixing the liquid vehicle with a sweetening agent and a surfactant.

[0506] Spray-dried dispersion

[0507] The methods and uses of the present disclosure may include administering a spray-dried dispersion (SDD) 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 the use of the SDD in the treatment of congenital adrenal hyperplasia (CAH).

[0508] In some embodiments, if the SDD exhibits one or more properties, enhanced concentration and bioavailability of a low solubility drug in an aqueous environment in a spray-dried dispersion are achieved, the 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 provides at least a transiently dissolved drug concentration in an aqueous environment that is greater than the solubility of the crystalline form of the drug in the same environment when administered to the aqueous environment. The aqueous environment can be, for example, an in vitro environment such as a dissolution test medium (e.g., phosphate buffered saline (PBS) solution), or an in vivo environment such as the gastrointestinal (GI) tract of an animal (e.g., a human). In some embodiments, the aqueous environment is the lower GI tract, such as the small intestine and the large intestine.

[0509] The present disclosure provides a spray-dried dispersion comprising a polymer and a compound having the structure of formula (I):

[0510]

[0511] or a pharmaceutically acceptable salt thereof. In some embodiments, the SDD comprises a polymer selected from neutral polymers, enteric polymers, and pyrrolidone polymers. 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.

[0512] 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 cellulose polymer. For example, the cellulose polymer can be a polymer having at least one substituent with an ester linkage and / or an ether linkage, wherein 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).

[0513] In some embodiments, the polymer is an enteric polymer. As used herein, an "enteric polymer" is a polymeric substance that is substantially insoluble and / or substantially stable under acidic conditions exhibiting a pH of less than about 7 and is substantially soluble or decomposable under conditions exhibiting a pH of about 7 or higher. Examples of suitable enteric polymers include, but are not limited to, carboxymethylethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), methyl cellulose phthalate, hydroxymethylethyl cellulose phthalate, hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), polyvinyl alcohol phthalate, polyvinyl butyral phthalate, polyvinyl acetal phthalate, copolymers of vinyl acetate / maleic anhydride, copolymers of vinyl butyl ether / maleic anhydride, copolymers of styrene / maleic monoester, copolymers of methyl acrylate / methacrylic acid, copolymers of styrene / acrylic acid, copolymers of methyl acrylate / methacrylic acid / octyl acrylate, copolymers of methacrylic acid / methyl methacrylate, amino methacrylate copolymers, ammonium alkyl methacrylate copolymers, methacrylic acid copolymers, and mixtures thereof. In some embodiments, the enteric polymer is selected from hydroxypropylmethyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP), amino methacrylate copolymers, ammonium alkyl methacrylate copolymers, and methacrylic acid copolymers. In some embodiments, the enteric polymer is a 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 E PO / 100. In some embodiments, the enteric polymer is an ammonium alkyl methacrylate copolymer. In some embodiments, the ammonium alkyl methacrylate copolymer is RLPO. In some embodiments, the enteric polymer is a methacrylic acid copolymer. In some embodiments, the methacrylic acid copolymer is L100 or S100.

[0514] In some embodiments, the polymer is a pyrrolidone polymer. For example, the pyrrolidone polymer can be a vinylpyrrolidone polymer, such as polyvinylpyrrolidone (PVP) or polyvinylpyrrolidone vinyl acetate (PVP / VA), including homopolymers and copolymers of PVP and homopolymers and copolymers of N-vinylpyrrolidone. In some embodiments, the pyrrolidone polymer is PVP / VA. In some embodiments, 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 in 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 in 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 in a ratio of about 60:40 by weight.

[0515] In some embodiments, the pyrrolidone polymer has the following structure:

[0516]

[0517] Wherein 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 the range defined by any of the foregoing 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.

[0518] In some embodiments, the pyrrolidone polymer has the following structure:

[0519]

[0520] Wherein the value of n is 1 to 2 times the value of m. For example, the value of n can be 1 time, 1.05 times, 1.1 times, 1.15 times, 1.16 times, 1.2 times, 1.25 times, 1.3 times, 1.35 times, 1.4 times, 1.45 times, 1.5 times, 1.55 times, 1.6 times, 1.65 times, 1.7 times, 1.75 times, 1.8 times, 1.85 times, 1.9 times, 1.95 times or 2 times the value of m, or a value within the range defined by any of the foregoing 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.

[0521] In some embodiments, relative to a control composition containing an equal amount of the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer for the disclosed SDD 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 use environment (e.g., an aqueous environment). In some embodiments, once the SDD is introduced into the use environment (e.g., an 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 understood that the control composition does not contain a solubilizer or other components that would substantially affect the solubility of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is in solid form in the control composition.

[0522] In some embodiments of the SDD, 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 from about 1:1 to about 1:8, from about 1:1 to about 1:7, from about 1:1 to about 1:6, from about 1:1 to about 1:5, from about 1:1 to about 1:4, from about 1:1 to about 1:3, from about 1:1 to about 1:2, from about 1:1 to about 1:1.5, from about 1:1.5 to about 1:9, or from 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 can be 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 the range defined by any of the foregoing 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.

[0523] In some embodiments of the SDD, 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 from 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 can be 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 the range defined by any of the foregoing 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.

[0524] In some embodiments, the spray-dried dispersion comprises 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, the copolymer having the following structure:

[0525]

[0526] wherein 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 in a ratio by weight of about 60:40, 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.

[0527] In some embodiments, the spray-dried dispersion comprises 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, the copolymer having the following structure:

[0528]

[0529] wherein the value of n is 1 to 2 times the value of m, and the copolymer contains 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio by weight of about 60:40, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the copolymer is 1:1 to 1:9.

[0530] In some embodiments of the SDD, the compound of formula (I) or a pharmaceutically acceptable salt and a polymer thereof together form uniform particles. In some embodiments, the particles are substantially homogeneous compositions that comprise the compound of formula (I) or a pharmaceutically acceptable salt and a polymer thereof. As used herein, "substantially homogeneous" means that the compound of formula (I) or a pharmaceutically acceptable salt thereof is dispersed as uniformly as possible throughout the polymer and can be considered a solid solution of the compound of formula (I) or a pharmaceutically acceptable salt thereof dispersed in the polymer. Although the dispersion may 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 indicates that the dispersion is substantially homogeneous. In contrast, 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 typically shows two different T g , one being the T g of the compound of formula (I) or a pharmaceutically acceptable salt thereof and one being the T g of the polymer. As used herein, "T g " is the characteristic temperature at which a glassy material undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glassy state to a rubbery state upon gradual heating.

[0531] In some embodiments, the particles have a size of from about 5 μm to about 100 μm, such as from about 5 μm to about 95 μm, from about 5 μm to about 90 μm, from about 5 μm to about 85 μm, from about 5 μm to about 80 μm, from about 5 μm to about 75 μm, from about 5 μm to about 70 μm, from about 5 μm to about 65 μm, from about 5 μm to about 60 μm, from about 5 μm to about 55 μm, from about 5 μm to about 50 μm, from about 5 μm to about 45 μm, from about 5 μm to about 40 μm, from about 5 μm to about 35 μm, from about 5 μm to about 30 μm, from about 5 μm to about 25 μm, from about 5 μm to about 20 μm, from about 5 μm to about 15 μm, from about 5 μm to about 10 μm, from about 10 μm to about 100 μm, from about 10 μm to about 95 μm, from about 10 μm to about 90 μm, from about 10 μm to about 85 μm, from about 10 μm to about 80 μm, from about 10 μm to about 75 μm, from about 10 μm to about 70 μm, from about 10 μm to about 65 μm, from about 10 μm to about 60 μm, from about 10 μm to about 55 μm, from about 10 μm to about 50 μm, from about 10 μm to about 45 μm, from about 10 μm to about 40 μm, from about 10 μm to about 35 μm, from about 10 μm to about 30 μm, from about 10 μm to about 25 μm, from about 10 μm to about 20 μm, from about 10 μm to about 15 μm, from about 15 μm to about 100 μm, from about 15 μm to about 95 μm, from about 15 μm to about 90 μm, from about 15 μm to about 85 μm, from about 15 μm to about 80 μm, from about 15 μm to about 75 μm, from about 15 μm to about 70 μm, from about 15 μm to about 65 μm, from about 15 μm to about 60 μm, from about 15 μm to about 55 μm, from about 15 μm to about 50 μm, from about 15 μm to about 45 μm, from about 15 μm to about 40 μm, from about 15 μm to about 35 μm, from about 15 μm to about 30 μm, from about 15 μm to about 25 μm, from about 15 μm to about 20 μm, from about 20 μm to about 100 μm, from about 20 μm to about 95 μm, from about 20 μm to about 90 μm, from about 20 μm to about 85 μm, from about 20 μm to about 80 μm, from about 20 μm to about 75 μm, from about 20 μm to about 70 μm, from about 20 μm to about 65 μm, from about 20 μm to about 60 μm, from about 20 μm to about 55 μm, from about 20 μm to about 50 μm, from about 20 μm to about 45 μm, from about 20 μm to about 40 μm, from about 20 μm to about 35 μm, from about 20 μm to about 30 μm, from about 20 μm to about 25 μm, from about 25 μm to about 100 μm, from about 25 μm to about 95 μm, from about 25 μm to about 90 μm, from about 25 μm to about 85 μm, from about 25 μm to about 80 μm, from about 25 μm to about 75 μm, from about 25 μm to about 70 μm, from about 25 μm to about 65 μm, from about 25 μm to about 60 μm, from about 25 μm to about 55 μm, from about 25 μm to about 50 μm, from about 25 μm to about 45 μm, from about 25 μm to about 40 μm,from about 25 μm to about 35 μm, from about 25 μm to about 30 μm, from about 30 μm to about 100 μm, from about 30 μm to about 95 μm, from about 30 μm to about 90 μm, from about 30 μm to about 85 μm, from about 30 μm to about 80 μm, from about 30 μm to about 75 μm, from about 30 μm to about 70 μm, from about 30 μm to about 65 μm, from about 30 μm to about 60 μm, from about 30 μm to about 55 μm, from about 30 μm to about 50 μm, from about 30 μm to about 45 μm, from about 30 μm to about 40 μm, from about 30 μm to about 35 μm, from about 35 μm to about 100 μm, from about 35 μm to about 95 μm, from about 35 μm to about 90 μm, from about 35 μm to about 85 μm, from about 35 μm to about 80 μm, from about 35 μm to about 75 μm, from about 35 μm to about 70 μm, from about 35 μm to about 65 μm, from about 35 μm to about 60 μm, from about 35 μm to about 55 μm, from about 35 μm to about 50 μm, from about 35 μm to about 45 μm, from about 35 μm to about 40 μm, from about 40 μm to about 100 μm, from about 40 μm to about 95 μm, from about 40 μm to about 90 μm, from about 40 μm to about 85 μm, from about 40 μm to about 80 μm, from about 40 μm to about 75 μm, from about 40 μm to about 70 μm, from about 40 μm to about 65 μm, from about 40 μm to about 60 μm, from about 40 μm to about 55 μm, from about 40 μm to about 50 μm, from about 40 μm to about 45 μm, from about 45 μm to about 100 μm, from about 45 μm to about 95 μm, from about 45 μm to about 90 μm, from about 45 μm to about 85 μm, from about 45 μm to about 80 μm, from about 45 μm to about 75 μm, from about 45 μm to about 70 μm, from about 45 μm to about 65 μm, from about 45 μm to about 60 μm, from about 45 μm to about 55 μm, from about 45 μm to about 50 μm, from about 50 μm to about 100 μm, from about 50 μm to about 95 μm, from about 50 μm to about 90 μm, from about 50 μm to about 85 μm, from about 50 μm to about 80 μm, from about 50 μm to about 75 μm, from about 50 μm to about 70 μm, from about 50 μm to about 65 μm, from about 50 μm to about 60 μm, from about 50 μm to about 55 μm, from about 55 μm to about 100 μm, from about 55 μm to about 95 μm, from about 55 μm to about 90 μm, from about 55 μm to about 85 μm, from about 55 μm to about 80 μm, from about 55 μm to about 75 μm, from about 55 μm to about 70 μm, from about 55 μm to about 65 μm, from about 55 μm to about 60 μm, from about 60 μm to about 100 μm, from about 60 μm to about 95 μm, from about 60 μm to about 90 μm, from about 60 μm to about 85 μm, from about 60 μm to about 80 μm, from about 60 μm to about 75 μm, from about 60 μm to about 70 μm, from about 60 μm to about 65 μm, from about 65 μm to about 100 μm, from about 65 μm to about 95 μm, from about 65 μm to about 90 μmA particle size distribution (D value, D) of from about 65 μm to about 85 μm, from about 65 μm to about 80 μm, from about 65 μm to about 75 μm, from about 65 μm to about 70 μm, from about 70 μm to about 100 μm, from about 70 μm to about 95 μm, from about 70 μm to about 90 μm, from about 70 μm to about 85 μm, from about 70 μm to about 80 μm, from about 70 μm to about 75 μm, from about 75 μm to about 100 μm, from about 75 μm to about 95 μm, from about 75 μm to about 90 μm, from about 75 μm to about 85 μm, from about 75 μm to about 80 μm, from about 80 μm to about 100 μm, from about 80 μm to about 95 μm, from about 80 μm to about 90 μm, from about 80 μm to about 85 μm, from about 85 μm to about 100 μm, from about 85 μm to about 95 μm, from about 85 μm to about 90 μm, from about 90 μm to about 100 μm, from about 90 μm to about 95 μm, or from about 95 μm to about 100 μm. 50 )。In some embodiments, 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, 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 the range defined by any of the foregoing values. In some embodiments, D 50 value is about 16 μm. The D 50 value can be measured by conventional particle size measurement 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.

[0532] In some embodiments, the particles have a size 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,Particle size distributions (D values, D) of 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. 50 ) In some embodiments, D 50is 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, D 50 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 foregoing values. In some embodiments, D 50 value is 16 μm. D 50 The value can be measured by conventional particle size measurement 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.

[0533] The SDDs of the present disclosure have a low residual solvent content. As used herein, "residual solvent content" refers to the amount of solvent present in the SDD after spray drying (immediately after being discharged from the spray dryer). The presence of solvent in the SDD reduces the glass transition temperature (T g)。In some embodiments, the mobility of the compound of formula (I) or its pharmaceutically acceptable salt in the SDD and its tendency to phase separate and crystallize decrease as the amount of residual solvent in the SDD decreases. In some embodiments, the SDD has a residual solvent content of no greater than about 10 wt%, such as no greater than about 5 wt%, or no greater than about 1 wt%. For example, the SDD has 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 lower. In some embodiments, the SDD has a residual solvent content of less than about 2 wt%. In some embodiments, the SDD has a residual solvent content of less than about 1 wt%. In some embodiments, the SDD has a residual solvent content of less than about 0.5 wt% or less. In some embodiments, the SDD has a residual solvent content of no greater than about 10 wt%, such as no greater than about 5 wt%, or no greater than about 1 wt%. For example, the SDD can 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 lower. In some embodiments, the SDD has a residual solvent content of less than 2 wt%. In some embodiments, the SDD has a residual solvent content of less than 1 wt%. In some embodiments, the SDD has a residual solvent content of 0.5 wt% or less.

[0534] 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 the amount of the 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 the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in crystalline form does not exceed 10 wt%. The amount of crystalline drug can be measured by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) analysis, differential scanning calorimetry (DSC), polarized light microscopy (PLM), or any other standard quantitative or qualitative measurement for detecting crystalline materials. Without wishing to be bound by any theory, it is believed that the amorphous or non-crystalline form in combination with the polymer results in easier dissolution and absorption at the desired location, e.g., in the intestine, leading to enhanced bioavailability compared to the crystalline form of the compound of formula (I) without the polymer.

[0535] Method for preparing spray-dried dispersion

[0536] Methods are provided in the present disclosure for preparing spray-dried dispersions (e.g., SDDs as described herein) comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises: 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 a spray-dried dispersion, wherein spray-drying forms uniform 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.

[0537] The SDDs disclosed herein can be obtained by spray-drying a mixture comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, one or more polymers, and a suitable solvent or solvent mixture. Spray-drying comprises atomizing a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and removing the solvent or solvent mixture. Atomization can be carried out, for example, by a two-fluid or pressure or electroacoustic nozzle or on a spinning disk.

[0538] Spray drying converts a liquid feed into a dried particulate form. In some embodiments, spray drying includes atomizing 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 equipment. In some embodiments, the composition is a clear solution free of undissolved solids. In some embodiments, the spray is generated by a rotary (wheel) or nozzle atomizer. Evaporation of water from the droplets and formation of dried particles occur under controlled temperature and gas flow conditions. Spray drying can be carried out using commercially available types of equipment. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro). The techniques and methods of spray drying can also be found in Perry’s Chemical Engineering Handbook, 6th Edition, 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).

[0539] In some embodiments, spray drying is carried out at an inlet temperature of about 40°C to about 100°C, such as about 60°C to about 80°C, or about 70°C to about 75°C. In some embodiments, spray drying is carried out at 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 foregoing values. In some embodiments, the inlet temperature is about 60°C to about 80°C. In some embodiments, spray drying is carried out at 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 foregoing values. In some embodiments, the inlet temperature is about 72°C.

[0540] In some embodiments, spray drying is carried out at an inlet temperature of 40°C to 100°C, such as 60°C to 80°C, or 70°C to 75°C. In some embodiments, spray drying is carried out at 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 an inlet temperature within a range defined by any of the foregoing values. In some embodiments, the inlet temperature is 60°C to 80°C. In some embodiments, spray drying is carried out at 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 an inlet temperature within a range defined by any of the foregoing values. In some embodiments, the inlet temperature is 72°C.

[0541] In some embodiments, spray drying is carried out at an outlet temperature of about 20°C to about 75°C, such as about 25°C to about 50°C, or about 30°C to about 40°C. In some embodiments, spray drying is carried out at 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 an outlet temperature within a range defined by any of the foregoing values. In some embodiments, the outlet temperature is about 25°C to about 45°C. In some embodiments, spray drying is carried out at 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 an outlet temperature within a range defined by any of the foregoing values. In some embodiments, the outlet temperature is about 35°C.

[0542] In some embodiments, spray drying is carried out at an outlet temperature of 20°C to 75°C, such as 25°C to 50°C, or 30°C to 40°C. In some embodiments, spray drying is carried out at 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 an outlet temperature within a range defined by any of the foregoing values. In some embodiments, the outlet temperature is 25°C to 45°C. In some embodiments, spray drying is carried out at 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 an outlet temperature within a range defined by any of the foregoing values. In some embodiments, the outlet temperature is 35°C.

[0543] In some embodiments, the method includes removing the organic solvent after forming the spray-dried dispersion. In some embodiments, the organic solvent is removed by drying the SDD. In some embodiments, a secondary drying method, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, drum drying, or double-cone vacuum drying, is used to remove the residual solvent or reduce the residual solvent to a pharmaceutically acceptable level, where the residual solvent is, for example, an organic solvent. In some embodiments, the SDD is dried using a convection tray dryer.

[0544] In some embodiments, the uniform 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 uniform 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 a bulk density within a range defined by any of the foregoing values. In some embodiments, the uniform 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 uniform 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 a bulk density within a range defined by any of the foregoing values. As used herein, the term "bulk density" refers to a property of a powder and is defined as the mass of many particles of a material divided by the total volume they occupy. The total volume includes the particle volume, the inter-particle void volume, and the internal pore volume.

[0545] In some embodiments, the uniform 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 uniform 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 a tapped density within the range defined by any of the foregoing values. In some embodiments, the uniform 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 uniform 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 a tapped density within the range defined by any of the foregoing values. As used herein, the term "tap density" or "tapped density" refers to a measure of the powder density. The tapped density of a pharmaceutical powder is determined using a tap density tester, which is set to tap the powder with a fixed impact force and frequency. The tapped density by the USP method is determined by a linear series of tap numbers.

[0546] Deuterated compound

[0547] Also disclosed herein are compounds having the structure of formula (II):

[0548]

[0549] or a pharmaceutically acceptable salt thereof, wherein:

[0550] Each R 1 is independently C(R A )3;

[0551] Each R A is independently hydrogen or deuterium;

[0552] Each R 2 is independently hydrogen or deuterium;

[0553] Each R 3 is independently hydrogen or deuterium;

[0554] R 4 is

[0555] R5 is hydrogen or deuterium;

[0556] R 6 is C(R A )3; and

[0557] R 7 is C(R B )3, where at least one of R A , R B , R 2 , R 3 and R 5 is deuterium.

[0558] With respect to the compounds provided herein, when a particular atomic position is specified as having deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is approximately 0.015%. In certain embodiments, the positions designated as having deuterium typically have a minimum isotopic enrichment factor of 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.

[0559] In some embodiments, the compound of formula (II) can be one of the following, or a pharmaceutically acceptable salt thereof:

[0560]

[0561] Pharmaceutical composition

[0562] The methods and uses disclosed herein can include administering a compound of formula (I) as a pharmaceutical composition.

[0563] In some embodiments of the methods 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 or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition that further comprises one or more pharmaceutically acceptable excipients.

[0564] The present invention also provides a pharmaceutical composition for any of the methods described herein, which comprises 4-(2-chloro-4-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.

[0565] In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is a spray-dried dispersion that does not contain a compound of formula (I), as specified, for example, in Example 1. Thus, in some embodiments, the pharmaceutical composition does not contain any of the following polymers: hypromellose acetate succinate-L (HPMCAS-L); polyvinylpyrrolidone vinyl acetate 64 (PVP / VA64): HPMCAS-M; and methacrylic acid methyl methacrylate copolymer (1:1) L100).

[0566] In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is not the reference formulation described in Example 9. Thus, in some embodiments, the pharmaceutical composition does not contain at least three excipients selected from caprylic / capric triglyceride ( Lipophile, Gattefossé, France); ethylene glycol dioctanoate / didecanoate ( PG, Gattefossé, France); glyceryl oleoyl polyoxyl-6 ( M 1944CS, Gattefossé, France); polysorbate 20; polyoxyl castor oil ( RH 40, BASF, Germany); polyoxyl 15 hydroxystearate ( HS15, BASF, Germany); lauroyl polyoxyl-32 glyceride ( 44 / 14, Gattefossé, France); d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); and diethylene glycol monoethyl ether ( Gattefossé, France).

[0567] In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is the formulation described in Example 9. In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is the formulation described in Example 11. In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is the formulation described in Example 12. In some embodiments, the methods and uses described herein include administering a pharmaceutical composition that is the formulation described in Example 13.

[0568] In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, the pharmaceutical composition comprises an SDD comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients. In some embodiments, the SDD is present in the composition at about 20% w / w to about 90% w / w of the composition, such as at 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%,Present in the pharmaceutical composition in an amount of 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. In some embodiments, SDD is present in the composition in an amount of about 40% w / w to about 90% w / w. In some embodiments, SDD is present in the composition in an amount of about 40% w / w to about 80% w / w. In some embodiments, SDD is present in the pharmaceutical composition in an amount of about 60% w / w to about 80% w / w. In some embodiments, SDD is present in the composition in an amount of about 80% w / w. In some embodiments, SDD is present in the pharmaceutical composition in an amount of about 1% w / w to about 20% w / w, such as about 13% w / w of the composition.

[0570] In some embodiments, the pharmaceutical composition comprises an SDD comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients. In some embodiments, the SDD is present in the composition in an amount of 20% w / w 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 in the pharmaceutical composition. In some embodiments, the SDD is present in the composition in an amount of 40% w / w to 90% w / w.In some embodiments, SDD is present in an amount of 40% w / w to 80% w / w of the composition. In some embodiments, SDD is present in an amount of 60% w / w to 80% w / w of the composition in the pharmaceutical composition. In some embodiments, SDD is present in an amount of 80% w / w of the composition. In some embodiments, SDD is present in an amount of about 1% w / w to about 20% w / w, such as about 13% w / w of the composition in the pharmaceutical composition.

[0571] In some embodiments of the pharmaceutical compositions disclosed herein (e.g., compositions comprising SDD), the pharmaceutically acceptable excipients are selected from fillers, lubricants, and combinations thereof. In some embodiments, the pharmaceutical excipients are selected from glidants, fillers, disintegrants, lubricants, and combinations thereof.

[0572] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the filler is selected from binders, diluents, disintegrants, glidants, surfactants, and combinations thereof.

[0573] In some embodiments, the filler includes saccharides (e.g., sugars, starches, and celluloses), gelatin, calcium carbonate, and synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene glycol, and poloxamers (e.g., poloxamer 188, a copolymer of polyethylene oxide and polypropylene oxide)). Exemplary fillers include, but are not limited to, glucose, sucrose, lactose, starch (including modified starches, such as sodium carboxymethyl starch (e.g., )), xylitol, dextrin, sucrose, sorbitol, mannitol (e.g., M 200 (mannitol having an average particle size of about 50 μm to about 500 μm) or M 100 (mannitol having an average particle size of less than 212 μm)), cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, calcium hydrogen phosphate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, alginic acid, alginates (e.g., sodium alginate), calcium silicate, and ion exchange resins. Exemplary cellulose fillers include microcrystalline cellulose (e.g., PH-101 (microcrystalline cellulose having an average particle size of about 50 μm) or Microcrystalline cellulose with an average particle size of about 180 μm), methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Exemplary fillers include cross-linked polyvinylpyrrolidone, such as polyvinylpyrrolidone with an average particle size of 90 μm to 130 μm, or polyvinylpyrrolidone with an average particle size of 10 μm to 30 μm. Other fillers known to those skilled in the art are also contemplated for formulating the pharmaceutical compositions described herein.

[0574] In some embodiments, the filler is a binder. Binders include agents that hold the active pharmaceutical ingredient (e.g., a spray-dried dispersion containing a polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof) and the inactive ingredients together as a cohesive mixture. Exemplary binders include, but are not limited to, glucose, sucrose, lactose, starch (including modified starches such as sodium carboxymethyl starch ), xylitol, dextrin, sucrose, sorbitol, mannitol (e.g., M 200 (mannitol with an average particle size of about 50 μm to about 500 μm), M 100 (mannitol with an average particle size less than 212 μm)), gelatin, tragacanth, acacia mucilage, cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and sodium carboxymethyl starch. Exemplary cellulose fillers include microcrystalline cellulose (e.g., PH-101 (microcrystalline cellulose with an average particle size of about 50 μm) or PH 200 (microcrystalline cellulose with an average particle size of about 180 μm)), cellulose ethers, methylcellulose, ethylcellulose, sodium cross-linked carboxymethylcellulose, sodium carboxymethylcellulose starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Exemplary polyvinylpyrrolidone fillers include cross-linked polyvinylpyrrolidone, such as CL (cross-linked povidone with an average particle size of 90 μm to 130 μm) or CL-SF (cross-linked povidone with an average particle size of 10 μm to 30 μm). Other binders known to those skilled in the art are also contemplated for formulating the pharmaceutical compositions described herein.

[0575] In some embodiments, the filler is a diluent. Suitable diluents include, but are not limited to, lactose, mannitol, isomaltulose, sucrose, dextrose, and sorbitol.

[0576] In some embodiments, the filler is a disintegrant. Disintegrants include any reagent that promotes the disintegration of the formulation in an aqueous environment, e.g., promoting more rapid release of the active pharmaceutical ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Exemplary disintegrants include, but are not limited to, starches and modified starches such as corn starch, potato starch, sodium starch glycolate or croscarmellose sodium, alginic acid, alginates (e.g., sodium alginate), polyvinylpyrrolidone, bentonite, methylcellulose, agar, carboxymethylcellulose, crospovidone, acid carbonate effervescent systems (e.g., citric acid with bicarbonate), and ion exchange resins. Other disintegrants known to those skilled in the art are also contemplated for formulating the pharmaceutical compositions described herein.

[0577] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the pharmaceutical composition comprises from about 1 w / w% to about 30 w / w% of a disintegrant. In some embodiments, the pharmaceutical composition comprises from about 5 w / w% to about 15 w / w% of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 10 w / w% of a disintegrant. In some embodiments, the disintegrant is selected from croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and sodium bicarbonate. In some embodiments, the disintegrant is croscarmellose sodium.

[0578] In some embodiments, the filler is a glidant. Glidants can be used to improve the flowability of powders or granules or both. Glidants include, but are not limited to, silica (e.g., colloidal silica or hydrated silica), magnesium silicate, magnesium aluminum silicate, talc, starch, calcium silicate, light anhydrous silicic acid, and silica aerogel.

[0579] In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / w% to about 5 w / w% of a glidant. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / w% to about 1 w / w% of a glidant. In some embodiments, the pharmaceutical composition comprises about 0.67 w / w% of a glidant. In some embodiments, the glidant is selected from calcium silicate, silica, and talc. In some embodiments, the glidant is calcium silicate.

[0580] In some embodiments, the filler is a surfactant, wetting agent, solubilizer, or a combination thereof. Examples include, but are not limited to, glyceryl monostearate, cetearyl alcohol, cetyl alcohol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers such as cetostearyl alcohol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., ) polyoxyethylene stearate, sodium lauryl sulfate, tyloxapol (an alkylaryl polyether alcohol type nonionic liquid polymer, also known as superinone or triton). Other examples include, but are not limited to, poloxamers such as F68, F127, and F108, which are block copolymers of ethylene oxide and propylene oxide; and polyamines such as 908 (also known as 908), which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF); dextran; lecithin; dialkyl esters of sulfosuccinic acid, such as OT, which is dioctyl sulfosuccinate (available from American Cyanimid); P, which is sodium lauryl sulfate (available from DuPont); X-200, which is an alkylaryl polyether sulfonate (available from Rohm and Haas); 20 and 80, which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals); Carbowax TM 3550 and 934, which are polyethylene glycols (available from Union Carbide); Crodesta TM F-110, which is a mixture of sucrose stearate and sucrose distearate, and Crodesta TM SL-40 (both available from Croda Inc.); and SA90HCO, which has the chemical formula C 18 H 37 —CH2(CON(CH3)CH2(CHOH)4CH2OH)2.

[0581] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the pharmaceutical composition comprises from about 30 w / w% to about 99 w / w% of a filler. In some embodiments, the pharmaceutical composition comprises from about 50 w / w% to about 90 w / w% of a filler. In some embodiments, the pharmaceutical composition comprises about 75.5 w / w% of a filler. In some embodiments, the filler is selected from mannitol, microcrystalline cellulose, lactose, starch, isomalt, siliconized microcrystalline cellulose, dicalcium phosphate, maltodextrin, and combinations thereof. In some embodiments, the filler is a combination of mannitol and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises from about 30 w / w% to about 80 w / w% of mannitol. In some embodiments, the pharmaceutical composition comprises from 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 from about 1 w / w% to about 50 w / w% of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises from 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.

[0582] In some embodiments, the pharmaceutical composition comprises a lubricant. A lubricant is a reagent added to a pharmaceutical formulation to reduce friction during processing and prevent the ingredients from aggregating 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), hydrogenated vegetable oil, mineral oil, polyethylene glycol, lycopodium powder, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium chloride, hydrogenated castor oil (sterotex), glyceryl monostearate, sodium stearyl fumarate, colloidal silica, sodium benzoate, sodium oleate, and sodium acetate. Other lubricants known to those skilled in the art are also contemplated for formulating the pharmaceutical compositions described herein.

[0583] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / w% to about 10 w / w% of a lubricant. In some embodiments, the pharmaceutical composition comprises from about 0.1 w / w% to about 1 w / w% of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5 w / w% of a lubricant. In some embodiments, the 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.

[0584] In some embodiments, the pharmaceutical composition comprises:

[0585] (a) a spray-dried dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a polymer;

[0586] (b) a glidant;

[0587] (c) a filler; and

[0588] (d) a disintegrant.

[0589] In some embodiments, the pharmaceutical composition comprises:

[0590] (a) about 1 w / w% to about 20 w / w% of a spray-dried dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a polymer;

[0591] (b) about 0.1 w / w% to about 1 w / w% of a glidant;

[0592] (d) about 50 w / w% to about 90 w / w% of a filler; and

[0593] (d) about 5 w / w% to about 0.2 w / w% of a disintegrant.

[0594] In some embodiments, the pharmaceutical composition comprises:

[0595] (a) about 13 w / w% of a spray-dried dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a polymer;

[0596] (b) about 0.67 w / w% of a glidant;

[0597] (c) about 75.5 w / w% of a filler; and

[0598] (d) about 10 w / w% of a disintegrant.

[0599] In some embodiments, the pharmaceutical composition comprises:

[0600] (a) the spray-dried dispersion of Example 3;

[0601] (b) calcium silicate;

[0602] (c) a combination of mannitol and microcrystalline cellulose; and

[0603] (d) croscarmellose sodium.

[0604] In some embodiments, the pharmaceutical composition comprises:

[0605] (a) about 1 w / w% to about 20 w / w% of the spray-dried dispersion of Example 3;

[0606] (b) about 0.1 w / w% to about 1 w / w% calcium silicate;

[0607] (c) about 50 w / w% to about 60 w / w% mannitol and about 10 w / w% to about 30 w / w% microcrystalline cellulose; and

[0608] (d) about 5 w / w% to about 0.2 w / w% sodium croscarmellose.

[0609] In some embodiments, the pharmaceutical composition comprises:

[0610] (a) about 13 w / w% of the spray-dried dispersion of Example 3;

[0611] (b) about 0.67 w / w% calcium silicate;

[0612] (c) about 56 w / w% mannitol and about 20 w / w% microcrystalline cellulose; and

[0613] (d) about 10 w / w% sodium croscarmellose.

[0614] The pharmaceutical formulations of the present disclosure may comprise additional excipients. Other examples of excipients include, but are not limited to, pigments, colorants, flavoring agents, preservatives, and sweetening agents. Flavoring agents and colorants may be added to improve the taste or appearance of the formulation. Examples of preservatives for pharmaceutical compositions are aromatic alcohols such as benzyl alcohol 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 methylparaben and propylparaben. Sweetening agents may be added to make the ingredients more palatable, especially in chewable tablets or liquids such as syrups.

[0615] Also provided is a method for preparing a pharmaceutical composition (such as the pharmaceutical composition of the present disclosure). In some embodiments, the method comprises combining the spray-dried dispersion described herein with one or more pharmaceutically acceptable excipients (such as the pharmaceutically acceptable excipients described herein).

[0616] In some embodiments, the method for preparing a pharmaceutical composition comprises:

[0617] (a) blending the spray-dried dispersion described herein with a glidant;

[0618] (b) further blending the blend of step (a) with a filler and a disintegrant;

[0619] (c) sieving the blend of step (b) to break up aggregates and facilitate the uniformity of the blend;

[0620] (d) Further admix the intragranular admixture of step (c);

[0621] (e) Compress the intragranular admixture of step (d) via roll compaction to form granules; and

[0622] (f) Grind the strip from roll compaction into the granules of step (e).

[0623] In some embodiments, the spray-dried dispersion is the spray-dried dispersion described in Example 3.

[0624] The pharmaceutical compositions of the present disclosure are formulated for oral administration. Any conventional pharmaceutical medium can be used in the preparation of the compositions for oral dosage forms. For solid oral preparations such as powders, capsules, cachets, soft capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants, etc. Suitable binders include, but are not limited to, starches, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth), or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starches, methylcellulose, agar, bentonite, xanthan gum, etc.

[0625] 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, cachet, soft capsule, granule, powder, sachet, melt bar, or melt film. In some embodiments, the solid dosage form is coated. In some embodiments, the coating is an enteric coating, sugar coating, or film coating. In some embodiments, the solid dosage form is a coated granule, coated tablet, enteric-coated tablet, or enteric-coated capsule. In some embodiments, the solid dosage form is a pill or tablet. Types of oral tablets include compressed, chewable lozenges and tablets, which can 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 oil, PEG, poloxamer 124, or triglyceride), or encapsulated in a capsule (gelatin or cellulose-based capsule). The capsule can be a hard or soft gelatin capsule, and the granules and powders can be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art.

[0626] The pharmaceutical compositions of the present disclosure can contain, per dosage unit (e.g., tablet, capsule, powder, etc.), an amount of the active ingredient necessary to deliver the effective dose as described above.

[0627] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated into unit dosage forms. 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 from about 5 mg to about 200 mg. For example, from about 5 mg to about 175 mg, from about 5 mg to about 150 mg, from about 5 mg to about 125 mg, from about 5 mg to about 100 mg, from about 5 mg to about 75 mg, from about 5 mg to about 50 mg, from about 5 mg to about 25 mg, from about 25 mg to about 200 mg, from about 25 mg to about 175 mg, from about 25 mg to about 150 mg, from about 25 mg to about 125 mg, from about 25 mg to about 100 mg, from about 25 mg to about 75 mg, from about 25 mg to about 50 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 50 mg to about 150 mg, from about 50 mg to about 125 mg, from about 50 mg to about 100 mg, from about 50 mg to about 75 mg, from about 75 mg to about 200 mg, from about 75 mg to about 175 mg, from about 75 mg to about 150 mg, from about 75 mg to about 125 mg, from about 75 mg to about 100 mg, from about 100 mg to about 200 mg, from about 100 mg to about 175 mg, from about 100 mg to about 150 mg, from about 100 mg to about 125 mg, from about 125 mg to about 200 mg, from about 125 mg to about 175 mg, from about 125 mg to about 150 mg, from about 150 mg to about 200 mg, from about 150 mg to about 175 mg, or from about 175 mg to about 200 mg is present in the unit dosage form. 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 from about 25 mg to about 125 mg. 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 from about 75 mg to about 150 mg. 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 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, or in an amount within the range defined by any of the foregoing values. 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. 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.. 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. 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 from 5 mg to 250 mg.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, 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 a unit dosage form. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of 25 mg to 125 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of 75 mg to 150 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a unit dosage form 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, or in an amount within a range defined by any of the foregoing values. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of 50 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of 100 mg. In some embodiments, the pharmaceutical composition of the present disclosure is formulated as a tablet. In some embodiments, the tablet is coated. In some embodiments, the pharmaceutical composition of the present disclosure is formulated as a capsule. In some embodiments, the pharmaceutical composition is in the form of a sachet. In some embodiments, the pharmaceutical composition is in the form of granules.

[0628] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at 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 at 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 at 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 at a dose of about 100 mg, based on the weight of the free base.

[0629] In some embodiments, the pharmaceutical composition is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 25 mg, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 50 mg, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 75 mg, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 100 mg, based on the weight of the free base.

[0630] 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.

[0631] The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition as described in the present disclosure can vary within a wide range from about 1.0 mg / adult / day to about 10,000 mg / adult / day or higher, or within any range therein. For oral administration, the composition can be provided in tablet form, which contains, 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 mg or about 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for symptomatic adjustment of the dose for the individual to be treated. In some embodiments, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be provided at a dose level from about 0.1 mg / kg body weight / day to about 1000 mg / kg body weight / day or within any range therein. For example, the range can be from about 0.5 mg / kg body weight / day to about 500 mg / kg body weight / day, from about 1.0 mg / kg body weight / day to about 250 mg / kg body weight / day, from about 0.1 mg / kg body weight / day to about 100 mg / kg body weight / day, from about 0.1 mg / kg body weight / day to about 50.0 mg / kg body weight / day, from about 0.1 mg / kg body weight / day to about 15.0 mg / kg body weight / day, from about 0.5 mg / kg body weight / day to about 7.5 mg / kg body weight / day, or any amount within the range. In some embodiments, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be provided at a dose level from 0.1 mg / kg body weight / day to 1000 mg / kg body weight / day or within any range therein. For example, the range can be from 0.5 mg / kg body weight / day to 500 mg / kg body weight / day, from 1.0 mg / kg body weight / day to 250 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 100 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 50.0 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 15.0 mg / kg body weight / day, from 0.5 mg / kg body weight / day to 7.5 mg / kg body weight / day, or any amount within the range. The pharmaceutical composition provided herein can be administered in a regimen of 1 to 4 times per day or as a single daily dose.

[0632] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 25 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 50 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 75 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 100 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 150 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, is about 200 mg.

[0633] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at 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 at 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 at 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 at a dose of about 100 mg, based on the weight of the free base.

[0634] In some embodiments, the pharmaceutical composition of the daily dose 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 pharmaceutical composition of the daily dose 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 pharmaceutical composition of the daily dose 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 pharmaceutical composition of the daily dose 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 pharmaceutical composition of the daily dose 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 pharmaceutical composition of the daily dose is about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0635] In some embodiments, the pharmaceutical composition is administered twice daily at a dose of about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered twice daily at a dose of about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered twice daily at a dose of about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition is administered twice daily at 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.

[0636] In some embodiments, the method comprises administering a pharmaceutical composition comprising a daily 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 a pharmaceutical composition comprising a daily 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 a pharmaceutical composition comprising a daily 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 a pharmaceutical composition comprising a daily 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. In some embodiments, the method comprises administering a pharmaceutical composition comprising a daily dose of 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 pharmaceutical composition comprising a daily dose of about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

[0637] In some embodiments, the method comprises administering the pharmaceutical composition twice daily at a dose of about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the method comprises administering the pharmaceutical composition twice daily at a dose of about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof twice daily at a dose of about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the method comprises administering the pharmaceutical composition twice daily at 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.

[0638] Factors related to the particular individual being treated, including the individual's age, weight, diet, and time of administration, may result in the need to adjust the dose. In some embodiments, the individual is an adult. In some embodiments, the individual is a pediatric individual.

[0639] Those skilled in the art will recognize that in vivo and in vitro tests using suitable, known, and generally accepted cell and / or animal models have predicted the ability of a test compound to treat or prevent a given disorder. Those skilled in the art will further recognize that in healthy individuals and / or those individuals suffering from a given disorder, human clinical trials can be completed according to methods well-known in the clinical and medical arts, including first-in-human trials, dose-range, and efficacy trials. For example, known methods can be used, including body weight, age, and models such as Child Simulation Modeling (CERTARA, Princeton, N.J.), which can be used to develop a pharmacokinetic method for dosing that takes into account the individual's age, the clearance pathway of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the body surface area (BSA).

[0640] 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, compared to the original composition after manufacture, the composition does not exhibit a change (e.g., greater than 5%) in appearance, pH, percentage of impurities, activity (measured by in vitro testing), or osmolarity over time (e.g., at least 3 months, 6 months, 9 months, or at least 12 months). In some embodiments, compared to the original pharmaceutical composition after manufacture, the pharmaceutical composition does not exhibit a significant change in one or more of appearance, pH, percentage of impurities, activity (measured by in vitro testing), or osmolarity over time (e.g., at least 12 months), as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

[0641] Kit

[0642] Kits are also provided. Generally, the kits include one or more pharmaceutical compositions as described herein, such as pharmaceutical compositions containing, for example, the spray-dried dispersions as described in Examples 1 to 4 or the formulations as described in Example 9. In certain embodiments, the kits can include, for example, one or more delivery systems for delivering or administering the pharmaceutical compositions provided herein, as well as instructions for use of the kits (e.g., instructions for treating an individual). In some embodiments, the kits can include the pharmaceutical compositions as described herein and a label indicating that the contents should be administered to an individual suffering from congenital adrenal hyperplasia. The actual dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof provided herein depends on the specific formulation, the weight of the patient, and the condition to be treated.

[0643] Example

[0644] Example 1: Spray-dried dispersion formulations containing the compound of formula (I) and various polymers

[0645] Spray-dried dispersion formulations

[0646] A series of spray-dried dispersion (SDD) formulations containing the compound of formula (I) and polymers were prepared. The SDD formulations included: (1) 10% compound of formula (I) / 90% hypromellose 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% polyvinylpyrrolidone vinyl acetate 64 (PVP / VA64); (5) 25% compound of formula (I) / 60% Cabosil (calcined 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) L100).

[0647] The PVP / VA polymer is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, with a 1-vinyl-2-pyrrolidone:vinyl acetate weight ratio of 60:40 and an average molecular weight of 45,000 to 70,000 (copovidone, VA 64 (sold by BASF, Florham Park, NJ). HPMCAS is a mixture of acetic acid and monosuccinate of hydroxypropyl methylcellulose, which is grade L (HPMCAS-L) with an acetyl content of 5% to 9%, a succinyl content of 14% to 18%, a methoxy content of 20% to 24%, and a hydroxypropoxy content of 5% to 9% (sold by Shin-Etsu, Japan); or grade M (HPMCAS-M) with an acetyl content of 7% to 11%, a succinyl content of 10% to 14%, a methoxy content of 21% to 25%, and a hydroxypropoxy content of 5% to 9% (sold by Shin-Etsu, Japan).

[0648] Dissolution properties

[0649] Test the dissolution properties of the above several SDD formulations (see Figure 1 ). Test various SDDs at 1000 μg A / mL in 0.5 wt% simulated intestinal fluid (SIF) in PBS (pH 6.5). Test the samples at 5, 10, 20, 45, 90, and 1200 minutes. Use a lipid formulation containing 10% of the compound of formula (I) as a control. The results are shown in Table 4 below.

[0650] Table 4. Dissolution data of various SDDs

[0651]

[0652] *Large differences between parallel tests, discard high values

[0653] Non-sedimenting dissolution

[0654] Perform membrane flux measurement (see, for example, Stewart et al., Mol. Pharm. (2017) 14:2032 - 2046), collect non-sedimenting dissolution data of the above several SDD formulations, and compare with the compound of formula (I) and several reference formulations (including a semi-solid lipid formulation (reference formulation 1) and two self-emulsifying drug delivery system (SEDDS) formulations (reference formulation 2 and reference formulation 3)). The components of the reference formulations are shown in Table 5 below, and in addition to the compound of formula (I), they also include triglyceride of caprylic / capric acid ( Lipophile, Gattefossé, France); dicaprylate / dicaprate of propylene glycol ( PG, Gattefossé, France); polyoxy-6 glycerol oleate ( M 1944CS, Gattefossé, France); polysorbate 20; polyoxyl castor oil ( RH 40, BASF, Germany); polyoxy 15 hydroxystearate( HS15, BASF, Germany); lauroyl polyoxy - 32 glycerol ester( 44 / 14, Gattefossé, France); d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); and diethylene glycol monoethyl ether( Gattefossé, France).

[0655] Table 5. Reference formulation (capsule)

[0656]

[0657] The assay measures the flux across the simulated gastric and intestinal walls via UV spectroscopy. Briefly, the assay is conducted as follows. A vertical membrane flux unit consisting of a donor compartment and a receiver compartment and separated by an Accurel PP 1E (55% porous, 100 μm thick) polypropylene membrane (3M, Maplewood, MN)( Figure 2 ) is impregnated with 50 μL of Pion GIT - 0 lipid solution consisting of 20% w / w phospholipid dissolved in dodecane (Pion Inc., Billerica, MA), and connected to the receiver vessel. Both the donor compartment and the receiver compartment are agitated by magnetic stirring. The receiver compartment contains plastic spacers and a grid to raise the stir bar above the membrane. The sample is introduced into the donor vessel by pre - weighing directly in the donor vessel and then adding the dissolution medium. Once the dissolution medium is added to the donor vessel, the receiver vessel is inserted into the donor vessel and vertically suspended 5 mm above the donor compartment through a plastic sleeve. For this assay, the simulated gastric (donor) medium is 0.1 N HCl (pH 2) and contains 200 μg A / mL of each SDD, and the simulated intestinal (receiver) medium is 0.5 wt% SIF in PBS (pH 6.5) and contains 100 μg A / mL of each SDD. The temperature for the assay is maintained at 44.5 °C. A UV probe (10 mm path length) is connected to a Rainbow UV spectrometer (Pion Inc.) system to measure the apparent drug concentration in the receiver vessel. Samples from the donor compartment are taken with a disposable pipette for centrifugation, and then the supernatant is analyzed by HPLC and DLS. The results are shown in Figure 3 and Table 6 below.

[0658] Table 6. Non - sedimenting dissolution data

[0659]

[0660]

[0661] The membrane fluxes of the compound of formula (I) at a dose of 1 mg / mL of gastric barrier / intestinal barrier (GB / IB) 0.5 wt% SIF and the 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 measured. The results are shown in Figure 4 as the receiver concentration versus time and the flux versus time (the smoothed derivative of the receiver concentration × volume / surface area) in

[0662] Example 2: Characterization of a spray-dried dispersion containing 25% of the compound of formula (I) and 75% polyvinylpyrrolidone vinyl acetate (PVP / VA) polymer

[0663] SDD Stability Screening

[0664] The chemical and physical stabilities of several SDDs described in Test Example 1 were tested. A wet SDD stability study was conducted, in which the samples were stored at 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 was correlated with the compound of formula (I) with a retention time of 32.36 minutes.

[0665] Table 7. Wet SDD Stability Data

[0666]

[0667]

[0668] LOQ = Limit of Quantification

[0669] A solution stability study was also conducted, in which the samples were stored at 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 was correlated with the compound of formula (I) with a retention time of 32.36 minutes.

[0670] Table 8. SDD Solution Stability Data

[0671]

[0672]

[0673] Stability studies were also conducted on SDDs containing 25% of the compound of formula (I) and 75% PVP / VA64, where the samples were stored at 5 °C (sealed with a desiccant), 25 °C (60% RH, sealed with a desiccant), and 30 °C (65% RH, sealed with a desiccant). Measurements were made after 1 month, 2 months, 3 months, 6 months, and 12 months of storage. No change in purity was observed after 12 months of storage. The results are shown in Table 9 below. The column was correlated with the compound of formula (I) and the retention time was 30.2 minutes.

[0674] Table 9. SDD Stability Data

[0675]

[0676]

[0677] Although Samples 1 and 2 showed degradation after approximately 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 chemically and physically stable and was further screened and characterized as described below.

[0678] 25% Formula (I) / 75% PVP / VA 64 SDD Process Parameter Screening Fabrication First Round

[0679] 25% Formula (I) / 75% PVP / VA 64 SDD was prepared on a pharmaceutical spray dryer with a drying gas capacity of 100 kg / hr (PSD-1). The fabrication overview is shown in Table 10 below.

[0680] Table 10. Fabrication Overview of Process Parameters

[0681]

[0682]

[0683] Based on the 73% yield observed in the first round of process screening, three sprays were conducted to study the effect of reducing the solution flux and outlet temperature on the product yield. All sprays were conducted at a reduced flow rate of 110 g / min. The outlet temperature was varied at 40 °C (Batch A), 35 °C (Batch B), and 30 °C (Batch C). The outlet temperature was reduced while maintaining a low outlet acetone saturation to increase the difference between the chamber outlet temperature and the wet SDD T g between, thereby increasing the product yield. The spray dryer chamber and outlet duct system were cleaned between all fabrications. The fabrication overview is shown in Table 11.

[0684] Table 11. Fabrication Overview of Process Parameters (1.5 kg Batch Size)

[0685]

[0686] It was found that the conditions for Batch B gave the highest yield. Then, one additional spray was carried out under the same process conditions as Batch B while increasing the batch size from 1.5 kg to 3.5 kg to evaluate process consistency and determine whether the product yield would continue to increase over time. The average process conditions for this batch are shown in Table 12.

[0687] Table 12. Manufacturing overview of process parameters (1.5 kg and 3.5 kg batch sizes)

[0688]

[0689] The yield of the 1.5 kg batch size (Batch D) spray was 84% compared to the 80% yield of the 3.5 kg batch (Batch B).

[0690] 25% Formula (I) / 75% PVP / VA 64SDD process parameter screening characterization

[0691] Characterization was performed to evaluate the powder properties, performance, and physical and chemical properties of 25% Formula (I) / 75% PVP / VA 64SDD manufactured for process parameters. The tests included determination of particle size distribution by Malvern, bulk density and tapped density, microcentrifuge dissolution, modulated differential scanning calorimetry (mDSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and determination of related substances. The results showed no significant differences between batches.

[0692] The particle size distribution (PSD) of 25% Formula (I) / 75% PVP / VA 64SDD and the listed powder property data are shown in Table 13. All 25% Formula (I) / 75% PVP / VA 64SDD were observed to have very similar PSDs, with row D 50 being approximately 16 μm. All 25% Formula (I) / 75% PVP / VA 64SDD were observed to have low bulk density and tapped density.

[0693] Table 13. Powder properties of process parameter screening NPVP / VA - 64SDD

[0694]

[0695] The batches with a 3.5 kg batch size were analyzed and compared with the process parameters of Batch A. The dissolution performance of each of these batches was similar. Dissolution rapidly reached C max , and high free drug was maintained within 90 minutes. These data are shown in Table 14.

[0696] Table 14. Dissolution properties of Batch A (1.5 kg batch size) relative to Batch D (3.5 kg batch size)

[0697]

[0698] 25% of formula (I) / 75% PVP / VA 64SDD was also evaluated by DSC, PXRD and SEM. The DSC thermogram showed a single T at 84 °C g , indicating a homogeneous dispersion. The PXRD diffraction pattern showed no evidence of crystals in the SDD. The SEM image showed an expanded spherical morphology, with some broken particles and some very small particles.

[0699] Additional tests were performed on Batch B, including evaluating the chemical / physical stability of both the spray solution and the SDD prior to secondary drying (wet SDD) to establish the maximum in-process hold time. The change in residual acetone concentration with secondary drying time in a convection tray dryer was also evaluated to specify the tray drying conditions, ensuring that the SDD was dry with acetone below the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

[0700] The change in residual acetone content with drying time was evaluated by drying the wet SDD in a tray dryer and collecting samples over 24 hours. The wet SDD was dried at 40 °C / 15% relative humidity (RH) and observed for 4 hours until dry below the ICH acetone guideline (0.5 wt%, 5000 ppm).

[0701] The spray solution hold time was determined by preparing a representative solution containing 2.5 wt% of the compound of formula (I), 7.5 wt% PVP / VA 64, and 90 wt% acetone. The related substances of these solutions were initially analyzed and then aged at 5 °C and 25 °C. Aliquots were taken and the related substances were analyzed periodically for 14 days. The results showed that the impurity profile did not change within 14 days under either condition.

[0702] After storage at 5 °C and 25 °C for 1 week and 2 weeks, the impurities in the wet SDD were analyzed and compared with the impurity profiles of the incoming compound of formula (I) and the SDD immediately after spray drying and prior to secondary drying. After 2 weeks of storage, the impurity profile was similar to that of the initial dried sample and the incoming compound of formula (I).

[0703] The physical stability of the wet SDD stability samples was characterized by DSC, PXRD and SEM. The DSC thermogram showed a single T at 81 °Cg , indicating a homogeneous dispersion with no phase separation. The PXRD diffraction pattern shows no evidence of any crystals after storage under any conditions. The SEM images show the typical morphology of mostly swollen spheres with some broken particles.

[0704] Example 3: Preparation of a spray-dried dispersion of a 1000 g batch containing 25% of the compound of formula (I) and 75% PVP / VA 64

[0705] A spray-dried dispersion of a 1000 g batch 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 batch and the 3.5 kg batch. Briefly, acetone (90% (w / w) of the total ...

Claims

1. A pharmaceutical composition in oral solution dosage form, comprising: (a) A 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) or a pharmaceutically acceptable salt thereof; (b) One or more of a sweetening agent, an antioxidant, and a flavoring agent; and (c) A liquid vehicle, wherein the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaprate, glycerol, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and diethylene glycol monoethyl ether.

2. The pharmaceutical composition according to claim 1, comprising (i) 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, (ii) about 1 w / v% to about 10 w / v% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or (iii) about 5 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 according to claim 1 or 2, comprising a sweetening agent.

4. The pharmaceutical composition according to claim 3, comprising (i) about 0.01 w / v% to about 1.5 w / v% of the sweetening agent, (ii) about 0.1 w / v% to about 0.5 w / v% of the sweetening agent, or (iii) about 0.15 w / v% of the sweetening agent.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the sweetening agent is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame.

6. The pharmaceutical composition according to claim 5, wherein the sweetening agent is saccharin.

7. The pharmaceutical composition according to any one of claims 1 to 6, comprising an antioxidant.

8. The pharmaceutical composition according to claim 7, comprising (i) about 0.01 w / v% to about 1.5 w / v% of the antioxidant, (ii) about 0.1 w / v% to about 0.5 w / v% of the antioxidant, or (iii) about 0.17 w / v% of the antioxidant.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antioxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone, and citric acid.

10. The pharmaceutical composition according to claim 9, wherein the antioxidant is butylated hydroxytoluene.

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising a flavoring agent.

12. The pharmaceutical composition according to claim 11, comprising (i) about 0.01 w / v% to about 0.5 w / v% of the flavoring agent, (ii) about 0.05 w / v% to about 0.2 w / v% of the flavoring agent, or (iii) about 0.10 w / v% of the flavoring agent.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the flavoring agent is selected from FONA orange flavoring agent, FONA fruit flavoring agent, FONA grape flavoring agent, Firmenich SA lemon flavoring agent, Firmenich Tetrarome orange flavoring agent, IFF cherry flavoring agent and IFF grape flavoring agent.

14. The pharmaceutical composition according to claim 13, wherein the flavoring agent is FONA orange flavoring agent.

15. The pharmaceutical composition according to any one of claims 1 to 14, which comprises (i) from about 50 w / v% to about 99.9 w / v% of the liquid vehicle, (ii) from about 90 w / v% to about 99 w / v% of the liquid vehicle, (ii) from about 92 w / v% to about 97 w / v% of the liquid vehicle, or (iv) about 94.6 w / v% of the liquid vehicle.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the liquid vehicle is medium chain triglyceride.

17. The pharmaceutical composition according to claim 16, wherein the medium chain triglyceride is caprylic / capric triglyceride.

18. The pharmaceutical composition according to any one of claims 1 to 17, which further comprises a surfactant.

19. The pharmaceutical composition according to claim 18, which comprises (i) from about 1 w / v% to about 50 w / v% of the surfactant, (ii) from about 10 w / v% to about 30 w / v% of the surfactant, or (iii) about 20 w / v% of the surfactant.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the surfactant is selected from oleoyl polyoxy-6 glyceride, linoleoyl polyoxy-6 glyceride, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, lauroyl polyoxy-32 glyceride, sodium lauryl sulfate, poloxamer, corn oil PEG-6 ester and hydrogenated palm / palm kernel oil PEG-6 ester.

21. The pharmaceutical composition according to claim 20, wherein the surfactant is oleoyl polyoxy-6 glyceride.

22. The pharmaceutical composition according to claim 21, wherein the oleoyl polyoxy-6 glyceride is LABRAFIL M1944CS.

23. The pharmaceutical composition according to any one of claims 1 to 22, which comprises (i) from about 70 w / v% to about 80 w / v% of the liquid vehicle, or (ii) about 75 w / v% of the liquid vehicle.

24. The pharmaceutical composition according to claim 1, which 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 sweetening agent; (c) an antioxidant; (d) a flavoring agent; and (e) a liquid vehicle.

25. The pharmaceutical composition according to claim 24, which further comprises a surfactant.

26. The pharmaceutical composition according to 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, in an amount of about 4 w / v% to about 6 w / v% based on the weight of the free base; (b) a sweetening agent in an amount of about 0.1 w / v% to about 0.2 w / v%; (c) an antioxidant in an amount of about 0.1 w / v% to about 0.2 w / v%; (d) a flavoring agent in an amount of about 0.05 w / v% to about 0.2 w / v%; and (e) a liquid vehicle in an amount of about 92 w / v% to about 97 w / v%.

27. The pharmaceutical composition according to 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, in an amount of about 5 w / v% based on the weight of the free base; (b) a sweetening agent in an amount of about 0.15 w / v%; (c) an antioxidant in an amount of about 0.17 w / v%; (d) a flavoring agent in an amount of about 0.1 w / v%; and (e) a liquid vehicle in an amount of about 94.6 w / v%.

28. The pharmaceutical composition according to 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, in an amount of about 4 w / v% to about 6 w / v% based on the weight of the free base; (b) a sweetening agent in an amount of about 0.1 w / v% to about 0.2 w / v%; (c) an antioxidant in an amount of about 0.1 w / v% to about 0.2 w / v%; (d) a flavoring agent in an amount of about 0.05 w / v% to about 0.2 w / v%; (e) a surfactant in an amount of about 15 w / v% to about 25 w / v%; and (f) a liquid vehicle in an amount of about 70 w / v% to about 80 w / v%.

29. The pharmaceutical composition according to 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, in an amount of about 5 w / v% based on the weight of the free base; (b) a sweetening agent in an amount of about 0.15 w / v%; (c) an antioxidant in an amount of about 0.17 w / v%; (d) a flavoring agent in an amount of about 0.1 w / v%; (e) a surfactant in an amount of about 20 w / v%; and (f) a liquid vehicle in an amount of about 75 w / v%.

30. The pharmaceutical composition according to claim 1, which 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 flavoring agent; and (e) Medium-chain triglycerides.

31. The pharmaceutical composition according to claim 30, which further comprises polyoxy-6 glyceryl oleate.

32. The pharmaceutical composition according to claim 30, 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 flavoring agent; and (e) About 92 w / v% to about 97 w / v% of medium-chain triglycerides.

33. The pharmaceutical composition according to 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 flavoring agent; and (e) About 94.6 w / v% of medium-chain triglycerides.

34. The pharmaceutical composition according to 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 flavoring agent; (e) About 15 w / v% to about 25 w / v% of polyoxy-6 glyceryl oleate; and (f) About 70 w / v% to about 80 w / v% of medium-chain triglycerides.

35. The pharmaceutical composition according to 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 flavoring agent; (e) About 20 w / v% of oleoyl polyoxy-6 glycerides; and (f) About 75 w / v% of medium-chain triglycerides.

36. The pharmaceutical composition according to any one of claims 1 to 35, which comprises the compound of formula (I) in free base form.

37. The pharmaceutical composition according to any one of claims 1 to 36, which is formulated into a unit dosage form, wherein (i) based on the weight of the free base, 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, (ii) based on the weight of the free base, 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, (iii) based on the weight of the free base, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 50 mg / mL, or (iv) based on the weight of the free base, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 100 mg / mL.

38. A method for preparing the pharmaceutical composition according to any one of claims 1 to 37, comprising: (a) mixing a liquid vehicle with a sweetening agent; (b) mixing the mixture of step (a) with an antioxidant and a flavoring agent; (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 another portion of the liquid vehicle.

39. The method according to claim 38, wherein step (a) comprises mixing a liquid vehicle with a sweetening agent and a surfactant.

40. Use of the pharmaceutical composition according to any one of claims 1 to 37 in the preparation of a medicament for the treatment of congenital adrenal hyperplasia (CAH) in an individual.

41. The use according to claim 40, wherein the individual is in a fed state.

42. The use according to claim 40 or 41, wherein the individual is administered the pharmaceutical composition and a nutritional composition.

43. The use according to claim 42, wherein the nutritional composition is a liquid dietary supplement containing about 1000 to about 2000 calories per liter and having a fat content greater than about 30%.

44. The use according to claim 43, wherein the nutritional composition is a liquid dietary supplement containing 1500 calories per liter and having a caloric distribution of 14.7% protein, 32% fat, and 53.3% carbohydrates.

45. The use according to any one of claims 42 to 44, wherein the nutritional composition is administered in an amount of about 6 to about 12 fluid ounces, or the nutritional composition is administered in an amount of about 8 fluid ounces.

46. The use according to any one of claims 42 to 45, wherein the nutritional composition is administered within 30 minutes of administering the pharmaceutical composition.

47. The use according to any one of claims 40 to 46, wherein administering the pharmaceutical composition exhibits a positive food effect.

48. The use according to claim 47, wherein when comparing oral administration of the pharmaceutical composition in the fed state and the fasted state, the positive food effect is measured in terms of C max , AUC or a combination thereof.

49. The use according to claim 48, 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.

50. The use according to claim 48, wherein the C of the compound of formula (I) in the fed state max and the C of the compound of formula (I) in the fasted state max has a ratio of from about 1 to about 4 or from about 5 to about 10.

51. The use according to claim 48, 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.

52. The use according to claim 48, wherein the C of the compound of formula (I) in the fed state max to the C of the compound of formula (I) in the fasted state max is from about 1.5 to about 3.

53. The use according to any one of claims 40 to 52, wherein the individual is a pediatric individual.

54. The use according to any one of claims 40 to 48, wherein when administered orally, the pharmaceutical composition exhibits a positive food effect.

55. The use according to claim 54, 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.

56. The use according to claim 54, wherein the C in the fed state of the compound of formula (I) max and the C in the fasted state max have a ratio of from about 1 to about 4 or from about 5 to about 10.

57. The use according to claim 54, 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.

58. The use according to claim 54, wherein the C in the fed state of the compound of formula (I) max and the C in the fasted state max have a ratio of from about 1.5 to about 3.

59. The use according to any one of claims 40 to 58, wherein the pharmaceutical composition is administered to the individual with a meal.

60. The use according to claim 61, wherein the meal is a high-fat meal, or the meal is a low-fat meal.

61. The use according to claim 59 or 60, wherein the pharmaceutical composition is administered within about 5 minutes after starting to eat the meal.

62. The use according to any one of claims 59 to 61, wherein the meal is dinner, or the meal is breakfast.

63. The use according to any one of claims 59 to 62, wherein administering the pharmaceutical composition exhibits a positive food effect.

64. The use according to claim 63, wherein when comparing the oral administration of the pharmaceutical composition in the fed state and the fasted state, the positive food effect is measured in terms of C max , AUC or a combination thereof of the compound of formula (I).

65. The use according to claim 64, 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.

66. The use according to claim 64, wherein the C of the compound of formula (I) in the fed state max to the C of the compound of formula (I) in the fasted state max is in the ratio of about 1 to about 4 or about 5 to about 10.

67. The use according to claim 64, 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.

68. The use according to claim 64, wherein the C of the compound of formula (I) in the fed state max and the C of the compound of formula (I) in the fasted state max has a ratio of about 1.5 to about 3.

69. The use according to any one of claims 40 to 68, wherein (i) based on the weight of the free base, the pharmaceutical composition comprises about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, (ii) 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, (iii) 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, or (iv) 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.

70. The use according to any one of claims 40 to 68, wherein the treatment comprises administering a daily dose of the pharmaceutical composition, and (i) 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, (ii) 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, (iii) 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, (iv) 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, (v) the pharmaceutical composition comprises about 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or, (vi) the pharmaceutical composition comprises about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

71. The use according to any one of claims 40 to 68, wherein the treatment comprises (i) administering the pharmaceutical composition twice daily at a dose of about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, (ii) administering the pharmaceutical composition twice daily at a dose of about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, (iii) administering the pharmaceutical composition twice daily at a dose of about 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or (iv) administering the pharmaceutical composition twice daily at 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.

72. The use according to any one of claims 40 to 71, wherein the individual receives a dose of glucocorticoid simultaneously.

73. The use according to claim 72, wherein the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate and desoxycorticosterone acetate.

74. The use according to claim 73, wherein the glucocorticoid is cortisol (hydrocortisone).

75. The use according to claim 73, wherein the glucocorticoid is cortisone.

76. The use according to claim 73, wherein the glucocorticoid is prednisone.

77. Use according to any one of claims 72 to 76, wherein the glucocorticoid dose is measured in hydrocortisone equivalents.

78. Use according to any one of claims 72 to 77, wherein the glucocorticoid dose measured in hydrocortisone equivalents is a multiple of the upper limit of the normal value of the physiological dose.

79. Use according to any one of claims 72 to 78, wherein the glucocorticoid dose is the physiological dose measured after a period of administration of the pharmaceutical composition.

80. Use according to any one of claims 72 to 79, wherein the glucocorticoid dose is (i) A physiological dose of from about 4 mg / m 2 / day to about 12 mg / m 2 / day, measured after a period of administration of the pharmaceutical composition, (ii) A physiological dose of about 4 mg / m 2 / day to about 9 mg / m 2 / day, measured after a period of administration of the pharmaceutical composition, or (iii) A physiological dose of less than about 8 mg / m 2 / day measured after a period of administration of the pharmaceutical composition.

81. Use according to any one of claims 72 to 80, wherein (i) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 10%, (ii) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 20%, (iii) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 30%, (iv) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 40%, (v) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 50%, (vi) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 60%, (vii) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 70%, (viii) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by less than about 20%, (ix) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by about 20% to about 50%, or (x) after a period of administration of the pharmaceutical composition, the glucocorticoid dose of the individual is reduced by more than about 50%, wherein the reduction in the glucocorticoid dose is relative to the glucocorticoid dose before administration of the pharmaceutical composition.

82. Use according to any one of claims 40 to 81, wherein (i) after a period of administration of the pharmaceutical composition, the level of 17 - hydroxyprogesterone is reduced by at least about 25%, wherein the reduction in the level of 17 - hydroxyprogesterone is relative to the level of 17 - hydroxyprogesterone before administration of the pharmaceutical composition, (ii) after a period of administration of the pharmaceutical composition, the level of 17 - hydroxyprogesterone is reduced by at least about 50%, wherein the reduction in the level of 17 - hydroxyprogesterone is relative to the level of 17 - hydroxyprogesterone before administration of the pharmaceutical composition, (iii) after a period of administration of the pharmaceutical composition, the level of 17 - hydroxyprogesterone is less than about 1.5 times the upper limit of the normal value, or (iv) after a period of administration of the pharmaceutical composition, the level of 17 - hydroxyprogesterone is within the normal limits.

83. Use according to any one of claims 40 to 82, wherein (i) After administration of the pharmaceutical composition for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 25%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (ii) After administration of the pharmaceutical composition for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 40%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (iii) After administration of the pharmaceutical composition for a period of time, the level of adrenocorticotropic hormone is reduced by at least about 50%, wherein the reduction in the level of adrenocorticotropic hormone is relative to the level of adrenocorticotropic hormone before administration of the pharmaceutical composition. (iv) After administration of the pharmaceutical composition for a period of time, the level of adrenocorticotropic hormone is less than about 1.5 times the upper limit of normal value, or (v) After administration of the pharmaceutical composition for a period of time, the level of adrenocorticotropic hormone is within the normal limits.

84. The use according to any one of claims 40 to 83, wherein (i) After administration of the pharmaceutical composition for a period of time, the level of androstenedione is reduced by at least about 25%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (ii) After administration of the pharmaceutical composition for a period of time, the level of androstenedione is reduced by at least about 30%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (iii) After administration of the pharmaceutical composition for a period of time, the level of androstenedione is reduced by at least about 50%, wherein the reduction in the level of androstenedione is relative to the level of androstenedione before administration of the pharmaceutical composition. (iv) After administration of the pharmaceutical composition for a period of time, the level of androstenedione is less than about 1.5 times the upper limit of normal value, or (v) After administration of the pharmaceutical composition for a period of time, the level of androstenedione is within the normal limits.

85. The use according to any one of claims 40 to 84, wherein (i) After administration of the pharmaceutical composition for a period of time, the level of testosterone is reduced by at least about 25%, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (ii) After administration of the pharmaceutical composition for a period of time, the level of testosterone is reduced by at least about 30%, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (iii) After administration of the pharmaceutical composition for a period of time, the level of testosterone is reduced by at least about 50%, wherein the reduction in the level of testosterone is relative to the level of testosterone before administration of the pharmaceutical composition. (iv) After administration of the pharmaceutical composition for a period of time, the level of testosterone is less than about 1.5 times the upper limit of normal value, or (v) After administration of the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, the level of testosterone is within normal limits.

86. Use according to any one of claims 40 to 85, wherein (i) after administration of the pharmaceutical composition for a period of time, the level of the 17-hydroxyprogesterone is reduced by at least about 50% and the level of androstenedione is reduced by at least about 50%, wherein the reduction in the level of the 17-hydroxyprogesterone and the level of androstenedione is relative to the level of the 17-hydroxyprogesterone and the level of androstenedione before administration of the pharmaceutical composition, (ii) after administration of the pharmaceutical composition for a period of time, the level of the 17-hydroxyprogesterone is less than about 1.5 times the upper limit of normal value and the level of androstenedione is less than about 1.5 times the upper limit of normal value, or (iii) after administration of the pharmaceutical composition for a period of time, the level of the 17-hydroxyprogesterone is within normal limits and the level of androstenedione is within normal limits.

87. Use according to any one of claims 72 to 86, wherein after administration of the pharmaceutical composition for a period of time, the individual exhibits a reduction in glucocorticoid load, wherein the reduction in glucocorticoid load is relative to the glucocorticoid load before administration of the pharmaceutical composition.

88. Use according to claim 87, wherein after administration of the pharmaceutical composition for a period of time, one or more symptoms of glucocorticoid load selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, body weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity and fertility are improved, wherein the improvement in the one or more symptoms is relative to the state of the one or more symptoms before administration of the pharmaceutical composition.

89. Use according to any one of claims 79 to 88, wherein (i) the period of administration is at least about 4 weeks, (ii) the period of administration is at least about 24 weeks, or (iii) the period of administration is at least about one year.

90. Use according to any one of claims 54 to 89, wherein the individual is a pediatric individual.

91. Use according to claim 53 or 90, wherein the pediatric individual (i) is less than or equal to six years old, (ii) is greater than six years old and less than eleven years old, (iii) is greater than ten years old and less than fifteen years old, or (iv) is greater than fourteen years old and less than nineteen years old.

92. Use according to any one of claims 40 to 52 or 54 to 89, wherein the individual is an adult individual.

93. Use according to claim 92, wherein the adult individual is greater than eighteen years old.

94. Use according to any one of claims 40 to 93, wherein the individual is female, or the individual is male.

95. Use according to any one of claims 40 to 94, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a hydrochloride salt or a p-toluenesulfonate salt.

96. The use according to any one of claims 40 to 95, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as 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-toluenesulfonate.

97. The use according to any one of claims 40 to 96, wherein the congenital adrenal hyperplasia (CAH) is classical CAH.

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