Methods for the administration of the orf antagonist crinecerfont and a strong cytochrome p4503a4 (CYP3a4) inducer

Abstract

Provided is a method of administering a selective corticotropin-releasing hormone receptor 1 (CRF1) receptor antagonist to a patient in need thereof, wherein the patient is being concomitantly administered a strong cytochrome P450 3A4 (CYP3A4) inducer.

Description

Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTMETHODS FOR THE ADMINISTRATION OF CRF ANTAGONISTTECHNICAL FIELD

[0001] The present disclosure relates to methods of administering 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2- ynyl-l,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, as well as pharmaceutical formulations thereof, to a patient, wherein the patient is being concomitantly administered a strong cytochrome P450 3 A4 (CYP3 A4) inducer.BACKGROUND

[0002] Classic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders that result in an enzyme deficiency that alters the production of adrenal steroids due to 21 -hydroxylase deficiency, a condition that results in little or no cortisol biosynthesis. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels cause adrenal hyperplasia and the enzyme mutation causes a shunting of cortisol precursor steroids to alternate pathways. Most notably, the shunting of androgens leads to virilization and other developmental complications in females and the overaccumulation of ACTH is associated with the formation of testicular adrenal rest tumors in males. In addition, since the same enzyme (21 -hydroxylase) is used in the pathway for the biosynthesis of the mineralocorticoids, a number of these patients suffer from aldosterone deficiency which can result in dehydration and death due to salt- wasting. For a long time, exogenous corticosteroids have been the standard of care for treating patients with classic CAH. This treatment is used to correct the cortisol deficiency and reduce the excessive ACTH levels and androgen excess. However, the dosage and duration of steroid use required to suppress ACTH are typically well above the normal physiological level used for cortisol replacement alone (as in patients with Addison’s disease). This increased exposure to glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth velocity, and decreased bone mineral density in CAH patients. Corticotropin releasing factor (CRF) is a hypothalamic hormone released directly into the hypophyseal portal vasculature and acts on specific corticotropin releasing factor 1 (CRF i) receptors on corticotropes in the anterior pituitary to stimulate the release of ACTH. Blockade of these receptors has been shown to decrease the release of ACTH in both animals and humans.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0003] Compound A, 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, (also referred to herein as crinecerfont) is a selective CRFi receptor antagonist that has been developed for the treatment of CAH associated with high ACTH levels and adrenal steroid insufficiency. Compound A, or a pharmaceutically acceptable salt thereof, can be prepared according to the methods described in WO 2021 / 252669 and U.S. Patent Nos. 6,586,456 and 8,314,249, each of which is hereby incorporated by reference in its entirety.

[0004] Crinecerfont is the first new treatment available in 70 years to the classic congenital adrenal hyperplasia (CAH) community that was approved by the US Food and Drug Administration (FDA) under the tradename CRENESSITY® in December 2024. Its approval was supported by data from the largest-ever clinical trial program in pediatric and adult patients with classic CAH. The data from the CAHtalyst™ Phase 3 global registrational studies in pediatric and adult patients with classic CAH were published in The New England Journal of Medicine (Sarafoglou, K., et al., New England Journal of Medicine, 391 (6), 493- 503 (Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia) and Auchus, R. J, et al., New England Journal of Medicine, 391 (6), 504-514 (Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia)). In the CAHtalyst™ pediatric phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with classic CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. In addition, in the CAHtalyst™ phase 3 trial of adults with classic CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. In both the pediatric and adult CAHtalyst™ studies, crinecerfont enabled lower steroid doses and decreased androgen levels, which led to the approval of CRENESSITY® by the FDA in December 2024. CRENESSITY® is approved as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH).

[0005] The cytochrome P450 enzyme system (CYP450) is responsible for the biotransformation of certain drugs from active substances to metabolites that can be excreted from the body.

[0006] There are more than 1500 known P450 sequences which are grouped into families and subfamily. The cytochrome P450 gene superfamily is composed of at least 207 genes thatAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT have been named based on the evolutionary relationships of the cytochromes P450. For this nomenclature system, the sequences of all of the cytochrome P450 genes are compared, and those cytochromes P450 that share at least 40% identity are defined as a family (designated by CYP followed by a Roman or Arabic numeral, e.g., CYP3), and further divided into subfamilies (designated by a capital letter, e.g., CYP3A), which are comprised of those forms that are at least 55% related by their deduced amino acid sequences. Finally, the gene for each individual form of cytochrome P450 is assigned an Arabic number (e.g., CYP3A4).

[0007] CYP3 A isoenzyme is a member of the cytochrome P450 superfamily which constitutes up to 60% of the total human liver microsomal cytochrome P450 and has been found in alimentary passage of stomach and intestines and livers. CYP3 A has also been found in kidney epithelial cells, jejunal mucosa, and the lungs.

[0008] At least five (5) forms of CYPs are found in the human CYP3 A subfamily, and these forms are at least partially responsible for the metabolism of a number of structurally diverse drugs. In non-induced individuals, CYP3A may constitute 15% of the P450 enzymes in the liver; in enterocytes, members of the CYP3 A subfamily constitute greater than 70% of the CYP-containing enzymes.

[0009] CYP3 A is at least partially responsible for metabolism of drugs including nifedipine, macrofide antibiotics including erythromycin and troleandomycin, cyclosporin, FK506, teffenadine, tamoxifen, lidocaine, midazolam, triazolam, dapsone, diltiazem, lovastatin, quinidine, ethylestradiol, testosterone, and alfentanil. CYP3 A is involved in erythromycin N- demethylation, cyclosporine oxidation, nifedipine oxidation, midazolam hydroxylation, testosterone 6-P-hydroxylation, and cortisol 6-P-hydroxylation. CYP3 A has also been shown to be involved in both bioactivation and detoxication pathways for several carcinogens in vitro.

[0010] When a drug substance being e.g., a CYP3A4 inducer, is administered to a subject, the substance increases the activity of the enzyme CYP3 A4, which means it enhances the enzyme's ability to break down other substances. This can lead to a decrease in the effectiveness of other drug substances that are metabolized by CYP3 A4, as they are cleared from the body more quickly.

[0011] There is a significant, unmet need for methods for treating CAH associated with high ACTH levels and adrenal steroid insufficiency wherein the patient is concomitantly being administered another substance which may interact with a CRFi receptor antagonist, such as a CYP3 A4 inducer. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTSUMMARY

[0012] Provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0013] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering an increased amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0014] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2- ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0015] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof,Attomey Docket No. 46696-0218WO 1 / 263.WO 1. PCT wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 400 mg (based on the weight of the free base) daily for an adult; about 400 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of > 55 kg; about 200 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0016] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 200 mg (based on the weight of the free base) twice daily for an adult; about 200 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0017] Also provided is a method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-l-Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from:- for an adult, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; and- for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0018] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A)Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT to a patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

[0019] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering an increased amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-A- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) to the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, wherein said increased amount of Compound A is increased with respect to the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

[0020] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2- ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; andAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0021] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 400 mg daily for an adult; about 400 mg daily for a pediatric patient having a body mass of > 55 kg; about 200 mg daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0022] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT about 200 mg twice daily for an adult; about 200 mg twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg-

[0023] Also provided is a method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (CompoundA),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A, is selected from:- for an adult, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening; and- for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0024] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTDETAILED DESCRIPTION

[0025] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0026] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0027] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0028] Compound A and its pharmaceutically acceptable salts may form solvates, including hydrates. Solvates are formed by the incorporation into the solid-state structure (e.g., crystal structure) of the compounds and salts described herein of molecules of a non-toxic pharmaceutically acceptable solvent. Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds and salts with a solvent, or a mixture of solvents, containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. The solvates can be stoichiometric or nonstoichiometric solvates. In some embodiments, the solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate.

[0029] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2%, and ± 1% of the stated value.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0030] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form or generally any amount of the drug compound into the patient via an art-recognized means of introduction.

[0031] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering off, reducing, or increasing the amount of the substance administered to the patient, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.

[0032] As used herein, "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0033] As used herein, "co-administer" and "co-administration" and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be coformulated as part of the same composition, or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.

[0034] As used herein, “amelioration of the symptoms” of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0035] As used herein, “baseline” refers to the period of time just prior to initiation of therapy. The patient's condition just prior to initiation of therapy can be referred to as the patient's baseline condition.

[0036] As used herein, the phrases “used concomitantly with” or “concomitantly using” or “concomitant use” refers to methods wherein the subject or patient is being concomitantly administered another drug substance or compound as specified.

[0037] As used herein the term "disorder" is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0038] As used herein, a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0039] As used herein, a “dosage form” refers to a form of the active agent suitable for administration of a specific dosage.

[0040] As used herein, a "dose" means the measured quantity of an active agent to be taken at one time by a patient

[0041] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0042] In the context of the present disclosure, the amount (as weight, typically in mg) of crinecerfont or a pharmaceutically acceptable salt thereof in a dosage form is always expressed as the equivalent amount of crinecerfont free base, regardless of the form used, i.e., the crinecerfont free base or a pharmaceutically acceptable salt. If a pharmaceutically acceptable salt of crinecerfont was used, the amount of the respective crinecerfont salt would be higher in order to match the equimolar amount of the crinecerfont free base form used.

[0043] As used herein, "increased amount" of an agent, compound, drug, composition, or combination is an amount, which is increased with respect to a therapeutically effective amount that would be administered to a subject or patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0044] As used herein, "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.

[0045] As used herein, "labeling" means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0046] As used herein, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0047] As used herein, “a medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.

[0048] As used herein, "Medication Guide" means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 C.F.R. §208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product. A medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 C.F.R. §201.57, but the language need not be identical to the sections of approved labeling to which it corresponds. A medication guide is typically available for a pharmaceutical product with special risk management information.

[0049] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0050] As used herein, a “pediatric” patient is from 4 years to less than 18 years of age.

[0051] As used herein, an “adult” or “adult patient” is 18 years of age or older.

[0052] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, / .< ., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. "Pharmacologically active" (or simply "active") as in a "pharmacologicallyAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0053] As used herein, in some embodiments, "pharmaceutically acceptable salt" refers to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Ver lag Helvetica Chimica Acta, Zurich, 2002 which is incorporated herein by reference in its entirety. The organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like. In some embodiments, "pharmaceutically acceptable salt" refers to base addition salts with an inorganic or an organic base. Inorganic bases which may be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates. Organic bases from which may be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, e.g., isopropylamine, trimethylamine, di ethylamine, tri ethylamine, tripropylamine, and ethanolamine.

[0054] As used herein, "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or itsAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0055] As used herein, a "product" or "pharmaceutical product" means a dosage form of an active agent plus published material, and optionally packaging.

[0056] As used herein, "product insert" means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.

[0057] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA or EMEA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as, for example indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.

[0058] As used herein, "published material" means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet popup window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0059] As used herein, "a strong cytochrome P450 3 A4 (CYP3 A4) inducer" or “a strong CYP3A4 inducer” means a substance that increases the activity of the enzyme CYP3A4, / .< ., a so-called CYP3 A4 inducer, by a certain amount. According to the “ICH harmonized guideline on Drug Interaction Studies” [https: / / database.ich.org / sites / default / files / ICH_M12_Step4_Guideline_2024_0521.pdf], which is hereby incorporated by reference in its entirety: If an investigational drug is a CYP inducer, it can be classified as a strong, moderate, or weak inducer based on its effect on a sensitive index CYP substrate. The convention is to categorize CYP induction in the following way: a strong inducer decreases the AUC of a sensitive index CYP substrate by 80%, a moderate inducer decreases the AUC of a sensitive index CYP substrate by 50 to < 80%, and a weak inducer decreases the AUC of a sensitive index CYP substrate by > 20 to < 50%.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTThese categories generally describe the effect of an investigational drug when given at the highest clinical dose and the shortest dosing interval within its therapeutic dose range / dosing regimen.

[0060] As used herein, the phrases “wherein the administration of Compound A (or a pharmaceutically acceptable salt thereof) improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient” or “wherein the administration of Compound A (or a pharmaceutically acceptable salt thereof) reduces androgen levels and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient” mean that the patient being administered Compound A (or a pharmaceutically acceptable salt thereof) demonstrates lower levels of androgens, including androstenedione, and / or demonstrates the ability to receive a reduced daily glucocorticoid dose compared to prior to starting treatment of Compound A.Methods of Treatment

[0061] Provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0062] In an embodiment thereof, the patient has congenital adrenal hyperplasia (CAH).

[0063] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering an increased amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0064] Also provided is a method of treating a patient with congenital adrenal hyperplasia(CAH), said method comprising: administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2- ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0065] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 400 mg (based on the weight of the free base) daily for an adult; about 400 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of > 55 kg; about 200 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0066] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is usedAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 200 mg (based on the weight of the free base) twice daily for an adult; about 200 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0067] Also provided is a method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l- (3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from:- for an adult, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT- for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; and- for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0068] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) to a patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

[0069] In an embodiment thereof, the patient has congenital adrenal hyperplasia (CAH).

[0070] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering an increased amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-A- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) to the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient,Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT wherein said increased amount of Compound A is increased with respect to the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

[0071] Also provided is a method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2- ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0072] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)- A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 400 mg daily for an adult;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT about 400 mg daily for a pediatric patient having a body mass of > 55 kg; about 200 mg daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0073] Also provided is a method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3- thiazol-2-amine (Compound A),(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 200 mg twice daily for an adult; about 200 mg twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg-

[0074] Also provided is a method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A, is selected from:- for an adult, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening;- for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening; and- for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0075] In some embodiments, Compound A is administered as the free base.

[0076] In some embodiments, Compound A is administered as a pharmaceutically acceptable salt.

[0077] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0078] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered twice daily, in the morning and in the evening.

[0079] In some embodiments, the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before or when not being concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer, is selected from the following:(A) for an adult, about 100 mg of Compound A (based on the weight of the free base) administered twice daily; for a pediatric patient having a body mass of > 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered twice daily; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 50 mg of Compound A (based on the weight of the free base) administered twice daily; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 25 mg of Compound A (based on the weight of the free base) administered twice daily;(B)Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT for an adult, about 100 mg of Compound A (based on the weight of the free base) administered in the morning and about 200 mg of Compound A (based on the weight of the free base) administered in the evening; for a pediatric patient having a body mass of > 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered in the morning and about 200 mg of Compound A (based on the weight of the free base) administered in the evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 50 mg of Compound A (based on the weight of the free base) administered in the morning and about 100 mg of Compound A (based on the weight of the free base) administered in the evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 25 mg of Compound A (based on the weight of the free base) administered in the morning and about 50 mg of Compound A (based on the weight of the free base) administered in the evening; and(C) for an adult, about 200 mg of Compound A (based on the weight of the free base) administered in the evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered in the evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered in the evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered in the evening.

[0080] Several dosing regimens for the administration of Compound A, or a pharmaceutically acceptable salt thereof, for a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer are described in published patent applications WO 2021 / 252669, WO 2024 / 206769 and WO 2024 / 233525, which are herewith incorporated by reference in their entireties.

[0081] In some embodiments, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double (2-fold) the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0082] In some embodiments, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased by about 50%, 60%, 70% , 80% or 90% of the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer, z.e., resulting in an increased amount of in total about 150%, 160%,Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT170% , 180% or 190% of the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0083] In some embodiments, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is 2.5-fold, 3-fold (triple), 3.5-fold, 4-fold or 5-fold the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0084] In some embodiments, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is only increased for one of the daily administrations in case of twice daily administration.

[0085] In some embodiments, the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

[0086] In some embodiments, the strong CYP3 A4 inducer is chosen from rifampicin, carbamazepine, phenytoin, and St. John's Wort.

[0087] In some embodiments, the patient is an adult and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 400 mg Compound A (based on the weight of the free base) daily.

[0088] In some embodiments, the patient is a pediatric patient weighing > 55 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 400 mg Compound A (based on the weight of the free base) daily.

[0089] In some embodiments, the patient is a pediatric patient weighing 20 kg to < 55 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 200 mg Compound A (based on the weight of the free base) daily.

[0090] In some embodiments, the patient is a pediatric patient weighing 10 kg to < 20 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 100 mg Compound A (based on the weight of the free base) daily.

[0091] In some embodiments, the patient is an adult and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 200 mg Compound A (based on the weight of the free base) twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0092] In some embodiments, the patient is a pediatric patient weighing > 55 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 200 mg Compound A (based on the weight of the free base) twice daily.

[0093] In some embodiments, the patient is a pediatric patient weighing 20 kg to < 55 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 100 mg Compound A (based on the weight of the free base) twice daily.

[0094] In some embodiments, the patient is a pediatric patient weighing 10 kg to < 20 kg and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered at an amount of about 50 mg Compound A (based on the weight of the free base) twice daily.

[0095] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0096] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

[0097] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered with a meal.

[0098] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

[0099] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

[0100] In some embodiments, the glucocorticoid replacement therapy is administered daily to the patient.

[0101] In some embodiments, the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

[0102] In some embodiments, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

[0103] In some embodiments, the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control in the patient. In some embodiments, the administration of Compound A, or a pharmaceutically acceptable salt thereof, enables a reduced glucocorticoid dose in the patient. In some embodiments, the administration ofCompound A, or a pharmaceutically acceptable salt thereof, enables a reduced glucocorticoid dose while maintaining androgen control in the patient. In some embodiments, theAttomey Docket No. 46696-0218WO 1 / 263.WO 1. PCT administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and enables a reduced glucocorticoid dose while maintaining androgen control in the patient. In some embodiments, the administration of Compound A, or a pharmaceutically acceptable salt thereof, enables androgen control in the patient.

[0104] In some embodiments, the patient is an adult patient. In some embodiments, the patient is a pediatric patient.

[0105] In some embodiments, the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH.

[0106] In some embodiments, the administration of Compound A, or a pharmaceutically acceptable salt thereof, reduces androgen levels and / or enables a reduced glucocorticoid dose while maintaining androgen control in adult patients with CAH.

[0107] In some embodiments, CAH is classic CAH.

[0108] In one embodiment, it is provided a method of treating an adult patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chl oro-4-methoxy-5 -methyl phenyl )- / f- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0109] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of > 55 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0110] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of 20 kg to < 55 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2- chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg of Compound A (based on theAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0111] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of 10 kg to < 20 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2- chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0112] In one embodiment, it is provided a method of treating an adult patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chl oro-4-methoxy-5 -methyl phenyl )- / f- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0113] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of > 55 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4- methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0114] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of 20 kg to < 55 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2- chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0115] In one embodiment, it is provided a method of treating a pediatric patient having a body mass of 10 kg to < 20 kg with classic congenital adrenal hyperplasia (CAH) using 4-(2- chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0116] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, may be used to treat or prevent adrenal myelolipoma in patients with CAH.

[0117] While it may be possible for the compounds and salts of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical formulations disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes. Exemplary pharmaceutical compositions are disclosedAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT in published patent application WO 2021 / 115555, which is hereby incorporated by reference in its entirety.

[0118] In one embodiment, a pharmaceutical composition for Compound A, or a pharmaceutically acceptable salt thereof, is in the form of a self-emulsifying drug delivery system formulation comprising an oily phase vehicle, a non-ionic surfactant, and optionally an emulsifying agent and / or a solubilizing agent.

[0119] In one embodiment, the formulation is in the form of a capsule.

[0120] In one embodiment, the pharmaceutical composition comprises(a) about 5 wt% to about 15 wt% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 35 wt% to about 45 wt% of an oily phase vehicle;(c) about 15 wt% to about 25 wt% of an emulsifying agent;(d) about 15 wt% to about 25 wt% of a nonionic surfactant; and(e) about 5 wt% to about 15 wt% of a solubilizing agent.

[0121] In one embodiment, the pharmaceutical composition comprises(a) about 10 wt% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 39 wt% of an oily phase vehicle;(c) about 20 wt% of an emulsifying agent;(d) about 19 wt% of a nonionic surfactant; and(e) about 11 wt% of a solubilizing agent.

[0122] In one embodiment, the oily phase vehicle is medium-chain triglycerides. In one embodiment, the medium-chain triglycerides are caprylic / capric triglycerides.

[0123] In one embodiment, the emulsifying agent is propylene glycol di capryl ate / di caprate.

[0124] In one embodiment, the non-ionic surfactant is lauroyl polyoxyl-32 glycerides.

[0125] In one embodiment, the solubilizing agent is vitamin E polyethylene glycol succinate.

[0126] In one embodiment, the pharmaceutical composition is in the form of a capsule and comprises 25 mg of Compound A, or a pharmaceutically acceptable salt thereof (based on the weight of the free base). In one embodiment, the pharmaceutical composition is in the form of a capsule and comprises 50 mg of Compound A, or a pharmaceutically acceptable salt thereof (based on the weight of the free base). In one embodiment, the pharmaceutical composition is in the form of a capsule and comprises 100 mg of Compound A, or a pharmaceutically acceptable salt thereof (based on the weight of the free base).Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0127] In one embodiment, when the patient is administered 200 mg of Compound A (based on the weight of the free base) at one time point AND if a pharmaceutical composition comprising 200 mg of Compound A (based on the weight of the free base) in one form does not exist, then the patient has to be administered two dosage forms of the pharmaceutical composition comprising 100 mg of Compound A, or a pharmaceutically acceptable salt thereof (based on the weight of the free base), at that time point.

[0128] In another embodiment, a pharmaceutical composition for Compound A, or a pharmaceutically acceptable salt thereof, is a liquid pharmaceutical composition in an oral solution dosage form comprising a liquid vehicle and one or more of a sweetener, an antioxidant, and a flavor, and optionally a surfactant.

[0129] In one embodiment, the liquid pharmaceutical composition comprises(a) about 4 w / v% to about 6 w / v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 0.1 w / v% to about 0.2 w / v% of a sweetener;(c) about 0.1 w / v% to about 0.2 w / v% of an anti-oxidant;(d) about 0.05 w / v% to about 0.2 w / v% of a flavor; and(e) about 92 w / v% to about 97 w / v% of a liquid vehicle.

[0130] In one embodiment thereof, the liquid pharmaceutical composition comprises(a) about 5 w / v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 0.15 w / v% of a sweetener;(c) about 0.17 w / v% of an anti-oxidant;(d) about 0.1 w / v% of a flavor; and(e) about 94.6 w / v% of a liquid vehicle.

[0131] In one embodiment, the liquid pharmaceutical composition comprises(a) about 4 w / v% to about 6 w / v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 0.1 w / v% to about 0.2 w / v% of a sweetener;(c) about 0.1 w / v% to about 0.2 w / v% of an anti-oxidant;(d) about 0.05 w / v% to about 0.2 w / v% of a flavor;(e) about 15 w / v% to about 25 w / v% of a surfactant; and(f) about 70 w / v% to about 80 w / v% of a liquid vehicle.

[0132] In one embodiment thereof, the liquid pharmaceutical composition comprisesAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(a) about 5 w / v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base;(b) about 0.15 w / v% of a sweetener;(c) about 0.17 w / v% of an anti-oxidant;(d) about 0.1 w / v% of a flavor;(e) about 20 w / v% of a surfactant; and(f) about 75 w / v% of a liquid vehicle.

[0133] In one embodiment, the sweetener is saccharin.

[0134] In one embodiment, the anti-oxidant is butylated hydroxytoluene.

[0135] In one embodiment, the flavor is an orange flavor.

[0136] In one embodiment, the surfactant is oleoyl polyoxyl-6-glycerides.

[0137] In one embodiment, the liquid vehicle is medium-chain triglycerides. In one embodiment, the medium-chain triglycerides are caprylic / capric triglycerides.

[0138] All the aforementioned embodiments for the methods of treatment according to the present disclosure are equally applicable to:Compound A, or a pharmaceutically acceptable salt thereof, for use in a method of treatment according to the present disclosure; the use of Compound A, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for a method of treatment according to the present disclosure; the use of Compound A, or a pharmaceutically acceptable salt thereof, in a method of treatment according to the present disclosure; the use of a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, in a method of treatment according to the present disclosure; or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, for use in a method of treatment according to the present disclosure.Some of these alternatives are depicted in the claims, which shall be considered to form part of the disclosure. Some of these aspects are further described in more detail below, but this description should not be construed as limiting.

[0139] The following embodiments represent alternative claim language for countries where method of treatment claims are not allowed and second medical use claims have to be in “for use” or in the so-called “Swiss type format”.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0140] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, is for use in a method of administration to a patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient; wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0141] In one embodiment thereof, the patient has congenital adrenal hyperplasia (CAH).

[0142] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising: administering an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0143] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), said treatment comprising: administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0144] In one embodiment thereof, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

[0145] In one embodiment thereof,- the patient is an adult, and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily,- the patient is a pediatric patient weighing > 55 kg, and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily,Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT- the patient is a pediatric patient weighing 20 kg to < 55 kg and, the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg Compound A (based on the weight of the free base) administered twice daily, or- the patient is a pediatric patient weighing 10 kg to < 20 kg, and the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg Compound A (based on the weight of the free base) administered twice daily.

[0146] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 400 mg (based on the weight of the free base) daily for an adult; about 400 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of > 55 kg; about 200 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0147] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(Compound A) or a pharmaceutically acceptable salt thereof, is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 200 mg (based on the weight of the free base) twice daily for an adult; about 200 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0148] In one embodiment thereof, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0149] In one embodiment thereof, Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

[0150] In one embodiment thereof, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

[0151] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A)Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT or a pharmaceutically acceptable salt thereof, is for use as an adjunctive treatment to glucocorticoid replacement therapy to control androgens in a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: for an adult, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

[0152] In one embodiment, the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

[0153] In one embodiment, the Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

[0154] In one embodiment, the glucocorticoid replacement therapy is administered daily to the patient.

[0155] In one embodiment, the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

[0156] In one embodiment, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0157] In one embodiment, the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

[0158] In one embodiment, the CAH is classic CAH.

[0159] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) is for use in a method of administration to a patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering an increased amount of Compound A to the patient; wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0160] In one embodiment thereof, the patient has congenital adrenal hyperplasia (CAH).

[0161] In another embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising: administering an increased amount of Compound A to the patient;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

[0162] In another embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), said treatment comprising: administering a therapeutically effective amount of Compound A to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A wherein said increased amount of Compound A is increased with respect to the therapeutically effective amount of Compound A administered to the patient before concomitantly using the strong cytochrome P450 3A4 (CYP3A4) inducer.

[0163] In an embodiment thereof, the increased amount of Compound A is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

[0164] In an embodiment thereof:- the patient is an adult, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily,- the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily,- the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A is about 100 mg Compound A administered twice daily, or- the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A is about 50 mg Compound A administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT

[0165] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A is selected from: about 400 mg daily for an adult; about 400 mg daily for a pediatric patient having a body mass of > 55 kg; about 200 mg daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

[0166] In one embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)- 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2- amine (Compound A),(Compound A) is for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 200 mg twice daily for an adult; about 200 mg twice daily for a pediatric patient having a body mass of > 55 kg;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT about 100 mg twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg-

[0167] In an embodiment thereof, Compound A is administered orally.

[0168] In an embodiment thereof, Compound A is administered with food.

[0169] In an embodiment thereof, Compound A is administered orally, twice daily with a meal in the morning and evening.

[0170] In another embodiment, the compound 4-(2-chloro-4-methoxy-5-methylphenyl)-7V- [(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) is for use as an adjunctive treatment to glucocorticoid replacement therapy to control androgens in a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A wherein the increased amount of Compound A is selected from: for an adult, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

[0171] In an embodiment, the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin,Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

[0172] In an embodiment, Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

[0173] In an embodiment, the glucocorticoid replacement therapy is administered daily to the patient.

[0174] In an embodiment, the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

[0175] In an embodiment, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

[0176] In an embodiment, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof

[0177] In an embodiment, the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

[0178] In an embodiment, the CAH is classic CAH.

[0179] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLESExample 1

[0180] In vitro, Compound A is metabolized primarily by CYP3 A4 (estimated fraction metabolized 68.0 to 83.7%). Based on the in vitro data that indicated that CYP3A is the highest contributor to overall metabolism, clinical studies were conducted to determine the potential for Compound A to be a “victim” of clinical drug-drug interactions resulting from CYP3 A4 / 5 induction (effect of rifampin, a strong CP3 A4 inducer).

[0181] Coadministration of rifampin with a single dose of a tosylate salt of Compound A decreased Compound A Cmax and AUCo-infby 23% and 62%, respectively (Table 1).Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTTable 1AUCo-tiast= area under the concentration versus time curve from 0 hours to last quantifiable concentration; AUCo-inf= area under the plasma concentration versus time curve from 0 hours to infinity; Cmax = maximum plasma concentration; CV = coefficient of variation; NC = not calculated; t = apparent terminal half-life; tmax = time to maximum plasma concentrationaParameters are reported as mean (CV%) except for tmax which is median (minimum, maximum).

[0182] With an observed reduction of 62% of Compound A AUC with rifampin, a strong CYP3 A4 inducer, the daily dose of Compound A should be doubled when administered with strong CYP3 A4 inducers to achieve typical plasma exposures in the absence of CYP3 A4 induction. Based on the observed relationship between Compound A exposure and efficacy response, any change in Compound A exposure due to concomitant use of a moderate or weak inducer of CYP3 A4 is unlikely to have a significant impact on the efficacy response of Compound A. No dose adjustment of Compound A is required when administered with moderate or weak CYP3 A4 inducers.

[0183] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and nonpatent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0184] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the fullAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCTWhat is claimed is:

1. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

2. The method of claim 1, wherein the patient has congenital adrenal hyperplasia (CAH).

3. The method of claim 1 or 2, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3A4) inducer.

4. The method of any one of the preceding claims, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT5. The method of any one of the preceding claims, wherein the patient is an adult, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.

6. The method of any one of claims 1 to 4, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.

7. The method of any one of claims 1 to 4, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg Compound A (based on the weight of the free base) administered twice daily.

8. The method of any one of claims 1 to 4, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg Compound A (based on the weight of the free base) administered twice daily.

9. The method of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

10. The method of claim 9, wherein the glucocorticoid replacement therapy is administered daily to the patient.

11. The method of claim 10, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

12. The method of claim 11, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT13. The method of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

14. The method of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

15. The method of any one of claims 1 to 12, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

16. The method of any one of the preceding claims, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

17. The method of any one of claims 2 to 16, wherein the CAH is classic CAH.

18. A method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering an increased amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A- prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the amount that would beAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

19. The method of claim 18, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

20. The method of claim 18 or 19, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

21. The method of any one of claims 18 to 20, wherein the patient is an adult, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.

22. The method of any one of claims 18 to 20, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.

23. The method of any one of claims 18 to 20, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg Compound A (based on the weight of the free base) administered twice daily.

24. The method of any one of claims 18 to 20, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg Compound A (based on the weight of the free base) administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT25. The method of any one of claims 18 to 24, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

26. The method of claim 25, wherein the glucocorticoid replacement therapy is administered daily to the patient.

27. The method of claim 26, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

28. The method of claim 27, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

29. The method of any one of claims 18 to 28, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

30. The method of any one of claims 18 to 29, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

31. The method of any one of claims 18 to 28, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

32. The method of any one of claims 18 to 31, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

33. The method of any one of claims 18 to 32, wherein the CAH is classic CAH.

34. A method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising:Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A- prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

35. The method of claim 34, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

36. The method of claim 34 or 35, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

37. The method of any one of claims 34 to 36, wherein the patient is an adult, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT38. The method of any one of claims 34 to 36, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily.

39. The method of any one of claims 34 to 36, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg Compound A (based on the weight of the free base) administered twice daily.

40. The method of any one of claims 34 to 36, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg Compound A (based on the weight of the free base) administered twice daily.

41. The method of any one of claims 34 to 40, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

42. The method of claim 41, wherein the glucocorticoid replacement therapy is administered daily to the patient.

43. The method of claim 42, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

44. The method of claim 43, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

45. The method of any one of claims 34 to 44, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

46. The method of any one of claims 34 to 45, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT47. The method of any one of claims 34 to 44, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

48. The method of any one of claims 34 to 47, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

49. The method of any one of claims 34 to 48, wherein the CAH is classic CAH.

50. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 400 mg (based on the weight of the free base) daily for an adult; about 400 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of > 55 kg; about 200 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 10 kg to < 20 kg.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT51. The method of claim 50, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

52. The method of claim 50 or 51, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

53. The method of claim 52, wherein the glucocorticoid replacement therapy is administered daily to the patient.

54. The method of claim 53, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

55. The method of claim 54, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

56. The method of any one of claims 50 to 55, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered twice daily.

57. The method of any one of claims 50 to 56, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

58. The method of any one of claims 50 to 57, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

59. The method of any one of claims 50 to 55, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

60. The method of any one of claims 50 to 59, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / orAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

61. The method of any one of claims 50 to 60, wherein the CAH is classic CAH.

62. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, to a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 200 mg (based on the weight of the free base) twice daily for an adult; about 200 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

63. The method of claim 62, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT64. The method of claim 62 or 63, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

65. The method of claim 64, wherein the glucocorticoid replacement therapy is administered daily to the patient.

66. The method of claim 65, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

67. The method of claim 66, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

68. The method of any one of claims 62 to 67, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

69. The method of any one of claims 62 to 68, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

70. The method of any one of claims 62 to 67, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, with a meal in the morning and evening.

71. The method of any one of claims 62 to 70, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

72. The method of any one of claims 62 to 71, wherein the CAH is classic CAH.

73. A method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(Compound A) or a pharmaceutically acceptable salt thereof, as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: for an adult, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

74. The method of claim 73, wherein the glucocorticoid replacement therapy is administered daily to the patient and comprises once daily administration or multiple daily administrations of a glucocorticoid.

75. The method of claim 74, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT76. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) to a patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

77. The method of claim 76, wherein the patient has congenital adrenal hyperplasia (CAH).

78. The method of claim 76 or 77, wherein the increased amount of Compound A is double the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

79. The method of any one of claims 76 to 78, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

80. The method of any one of claims 76 to 79, wherein the patient is an adult, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT81. The method of any one of claims 76 to 79, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.

82. The method of any one of claims 76 to 79, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A is about 100 mg Compound A administered twice daily.

83. The method of any one of claims 76 to 79, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A is about 50 mg Compound A administered twice daily.

84. The method of any one of claims 76 to 83, wherein Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

85. The method of claim 84, wherein the glucocorticoid replacement therapy is administered daily to the patient.

86. The method of claim 85, wherein glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

87. The method of claim 86, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

88. The method of any one of claims 76 to 87, wherein Compound A is administered orally.

89. The method of any one of claims 76 to 88, wherein Compound A is administered with food.

90. The method of any one of claims 76 to 87, wherein Compound A is administered orally, twice daily with a meal in the morning and evening.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT91. The method of any one of claims 76 to 90, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

92. The method of any one of claims 77 to 91, wherein the CAH is classic CAH.

93. A method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering an increased amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A- prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) to the patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, wherein said increased amount of Compound A is increased with respect to the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

94. The method of claim 93, wherein the increased amount of Compound A is double the amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

95. The method of claim 93 or 94, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

96. The method of any one of claims 93 to 95, wherein the patient is an adult, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT97. The method of any one of claims 93 to 95, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.

98. The method of any one of claims 93 to 95, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A is about 100 mg Compound A administered twice daily.

99. The method of any one of claims 93 to 95, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A is about 50 mg Compound A administered twice daily.

100. The method of any one of claims 93 to 99, wherein Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

101. The method of claim 100, wherein the glucocorticoid replacement therapy is administered daily to the patient.

102. The method of claim 101, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

103. The method of claim 102, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

104. The method of any one of claims 93 to 103, wherein Compound A is administered orally.

105. The method of any one of claims 93 to 104, wherein Compound A is administered with food.

106. The method of any one of claims 93 to 103, wherein Compound A is administered orally, twice daily with a meal in the morning and evening.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT107. The method of any one of claims 93 to 106, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

108. The method of any one of claims 93 to 107, wherein the CAH is classic CAH.

109. A method of treating a patient with congenital adrenal hyperplasia (CAH), said method comprising: administering a therapeutically effective amount of 4-(2-chloro-4-methoxy-5- methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A- prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, wherein said increased amount of Compound A is increased with respect to the therapeutically effective amount of Compound A administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

110. The method of claim 109, wherein the increased amount of Compound A is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

111. The method of claim 109 or 110, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT112. The method of any one of claims 109 to 111, wherein the patient is an adult, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.

113. The method of any one of claims 109 to 111, wherein the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily.

114. The method of any one of claims 109 to 111, wherein the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A is about 100 mg Compound A administered twice daily.

115. The method of any one of claims 109 to 111, wherein the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A is about 50 mg Compound A administered twice daily.

116. The method of any one of claims 109 to 115, wherein Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

117. The method of claim 116, wherein the glucocorticoid replacement therapy is administered daily to the patient.

118. The method of claim 117, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

119. The method of claim 118, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

120. The method of any one of claims 109 to 119, wherein Compound A is administered orally.

121. The method of any one of claims 109 to 120, wherein Compound A is administered with food.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT122. The method of any one of claims 109 to 119, wherein Compound A is administered orally, twice daily with a meal in the morning and evening.

123. The method of any one of claims 109 to 122, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

124. The method of any one of claims 109 to 123, wherein the CAH is classic CAH.

125. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 400 mg daily for an adult; about 400 mg daily for a pediatric patient having a body mass of > 55 kg; about 200 mg daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg daily for a pediatric patient having a body mass of 10 kg to < 20 kg-126. The method of claim 125, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT127. The method of claim 125 or 126, wherein Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

128. The method of claim 127, wherein the glucocorticoid replacement therapy is administered daily to the patient.

129. The method of claim 128, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

130. The method of claim 129, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

131. The method of any one of claims 125 to 130, wherein Compound A is administered twice daily.

132. The method of any one of claims 125 to 131, wherein Compound A is administered orally.

133. The method of any one of claims 125 to 132, wherein Compound A is administered with food.

134. The method of any one of claims 125 to 131, wherein Compound A is administered orally, twice daily with a meal in the morning and evening.

135. The method of any one of claims 125 to 134, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

136. The method of any one of claims 125 to 135, wherein the CAH is classic CAH.

137. A method of administering 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2- cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol- 2-amine (Compound A),Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(Compound A) to a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 200 mg twice daily for an adult; about 200 mg twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

138. The method of claim 137, wherein the strong CYP3A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John's wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

139. The method of claim 137 or 138, wherein Compound A is administered as an adjunctive treatment to glucocorticoid replacement therapy.

140. The method of claim 139, wherein the glucocorticoid replacement therapy is administered daily to the patient.

141. The method of claim 140, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT142. The method of claim 141, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

143. The method of any one of claims 137 to 142, wherein Compound A is administered orally.

144. The method of any one of claims 137 to 143, wherein Compound A is administered with food.

145. The method of any one of claims 137 to 142, wherein Compound A is administered orally, with a meal in the morning and evening.

146. The method of any one of claims 137 to 145, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

147. The method of any one of claims 137 to 146, wherein the CAH is classic CAH.

148. A method of treating a patient with classic congenital adrenal hyperplasia (CAH) using 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(15)-2-cyclopropyl-l-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) as adjunctive treatment to glucocorticoid replacement therapy to control androgens in the patient, when Compound A is used concomitantly with a strong cytochrome P4503 A4 (CYP3 A4) inducer in the patient, said method comprising: administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: for an adult, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening;Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

149. The method of claim 148, wherein the glucocorticoid replacement therapy is administered daily to the patient and comprises once daily administration or multiple daily administrations of a glucocorticoid.

150. The method of claim 149, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

151. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, for use in a method of administration to a patient, when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient; wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would beAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

152. The compound for use according to claim 151, wherein the patient has congenital adrenal hyperplasia (CAH).

153. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising: administering an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient; wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3A4 (CYP3A4) inducer.

154. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A)Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), said treatment comprising: administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein said increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is increased with respect to the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.

155. The compound for use according to any one of claims 151 to 154, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

156. The compound for use according to any one of claims 151 to 155, wherein- the patient is an adult, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily,- the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg Compound A (based on the weight of the free base) administered twice daily,- the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg Compound A (based on the weight of the free base) administered twice daily, or- the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 50 mg Compound A (based on the weight of the free base) administered twice daily.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT157. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 400 mg (based on the weight of the free base) daily for an adult; about 400 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of > 55 kg; about 200 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 100 mg (based on the weight of the free base) daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

158. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A, or a pharmaceuticallyAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: about 200 mg (based on the weight of the free base) twice daily for an adult; about 200 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg (based on the weight of the free base) twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

159. The compound for use according to any one of claims 151 to 158, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

160. The compound for use according to any one of claims 151 to 159, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

161. The compound for use according to any one of claims 151 to 158, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally, twice daily with a meal in the morning and evening.

162. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) or a pharmaceutically acceptable salt thereof, for use as an adjunctive treatment to glucocorticoid replacement therapy to control androgens in a patient with congenitalAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT adrenal hyperplasia (CAH), when Compound A, or a pharmaceutically acceptable salt thereof, is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A, or a pharmaceutically acceptable salt thereof, is selected from: for an adult, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A (based on the weight of the free base) administered orally, twice daily with a meal in the morning and evening.

163. The compound for use according to any one of claims 151 to 162, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

164. The compound for use according to any one of claims 151 to 163, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered as an adjunctive treatment to glucocorticoid replacement therapy.

165. The compound for use according to claim 164, wherein the glucocorticoid replacement therapy is administered daily to the patient.

166. The compound for use according to claim 165, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT167. The compound for use according to claim 166, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

168. The compound for use according to any one of claims 151 to 167, wherein the administration of Compound A, or a pharmaceutically acceptable salt thereof, improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

169. The compound for use according to any one of claims 152 to 168, wherein the CAH is classic CAH.

170. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) for use in a method of administration to a patient, when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said method comprising: administering an increased amount of Compound A to the patient; wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

171. The compound for use according to claim 170, wherein the patient has congenital adrenal hyperplasia (CAH).

172. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT(Compound A) for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising: administering an increased amount of Compound A to the patient; wherein said increased amount of Compound A is increased with respect to an amount that would be administered to a patient not concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

173. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lA)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), said treatment comprising: administering a therapeutically effective amount of Compound A to the patient, subsequently initiating concomitant use of a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient; and administering to the patient an increased amount of Compound A wherein said increased amount of Compound A is increased with respect to the therapeutically effective amount of Compound A administered to the patient before concomitantly using the strong cytochrome P450 3 A4 (CYP3 A4) inducer.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT174. The compound for use according to any one of claims 170 to 173, wherein the increased amount of Compound A is double the amount administered to the patient before concomitantly using a strong cytochrome P450 3 A4 (CYP3 A4) inducer.

175. The compound for use according to any one of claims 170 to 174, wherein- the patient is an adult, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily,- the patient is a pediatric patient weighing > 55 kg, and wherein the increased amount of Compound A is about 200 mg Compound A administered twice daily,- the patient is a pediatric patient weighing 20 kg to < 55 kg and, wherein the increased amount of Compound A is about 100 mg Compound A administered twice daily, or- the patient is a pediatric patient weighing 10 kg to < 20 kg, and wherein the increased amount of Compound A is about 50 mg Compound A administered twice daily.

176. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-A-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the increased amount of Compound A is selected from: about 400 mg daily for an adult; about 400 mg daily for a pediatric patient having a body mass of > 55 kg; about 200 mg daily for a pediatric patient having a body mass of 20 kg to < 55 kg; andAttorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT about 100 mg daily for a pediatric patient having a body mass of 10 kg to < 20 kg-177. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lA)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) for use in the treatment of a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A, wherein the increased amount of Compound A is selected from: about 200 mg twice daily for an adult; about 200 mg twice daily for a pediatric patient having a body mass of > 55 kg; about 100 mg twice daily for a pediatric patient having a body mass of 20 kg to < 55 kg; and about 50 mg twice daily for a pediatric patient having a body mass of 10 kg to < 20 kg.

178. The compound for use according to any one of claims 170 to 177, wherein Compound A is administered orally.

179. The compound for use according to any one of claims 170 to 178, wherein Compound A is administered with food.

180. The compound for use according to any one of claims 170 to 179, wherein Compound A is administered orally, twice daily with a meal in the morning and evening.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT181. The compound 4-(2-chloro-4-methoxy-5-methylphenyl)-A-[(lN)-2-cyclopropyl-l-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound A),(Compound A) for use as an adjunctive treatment to glucocorticoid replacement therapy to control androgens in a patient with congenital adrenal hyperplasia (CAH), when Compound A is used concomitantly with a strong cytochrome P450 3 A4 (CYP3 A4) inducer in the patient, said treatment comprising administering to the patient an increased amount of Compound A wherein the increased amount of Compound A is selected from: for an adult, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of > 55 kg, about 200 mg of Compound A administered orally, twice daily with a meal in the morning and evening; for a pediatric patient having a body mass of 20 kg to < 55 kg, about 100 mg of Compound A administered orally, twice daily with a meal in the morning and evening; and for a pediatric patient having a body mass of 10 kg to < 20 kg, about 50 mg of Compound A administered orally, twice daily with a meal in the morning and evening.

182. The compound for use according to any one of claims 170 to 181, wherein the strong CYP3 A4 inducer is chosen from rifampicin, apalutamide, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, enzalutamide, lumacaftor, St. John’s wort, mitotane, nevirapine, rimexolone, rifaximin, rifabutin, rifamycin, midostaurin, and rifapentine.

183. The compound for use according to any one of claims 170 to 182, wherein CompoundA is administered as an adjunctive treatment to glucocorticoid replacement therapy.Attorney Docket No. 46696-0218WO 1 / 263.WO 1. PCT184. The compound for use according claim 183, wherein the glucocorticoid replacement therapy is administered daily to the patient.

185. The compound for use according to claim 184, wherein the glucocorticoid replacement therapy comprises once daily administration or multiple daily administrations of a glucocorticoid.

186. The compound for use according to claim 185, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

187. The compound for use according to any one of claims 170 to 186, wherein the administration of Compound A improves androgen control and / or enables a reduced glucocorticoid dose while maintaining androgen control in the patient.

188. The compound for use according to any one of claims 170 to 187, wherein the CAH is classic CAH.

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