Melanocortin-subtype-2 receptor (MC2R) antagonists for the treatment of diseases

Abstract

To provide a composition for the treatment of diseases of ACTH excess such as Cushing's disease, ectopic ACTH syndrome, and congenital adrenal hyperplasia.SOLUTION: Provided is a pharmaceutical composition for use in a method of treating congenital adrenal hyperplasia (CAH) in a human comprising a compound having the structure of Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein the method comprises administering the pharmaceutical composition to the human in need thereof.SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 163,310, filed March 19, 2021, and U.S. Provisional Patent Application No. 63 / 298,571, filed January 11, 2022, each of which is incorporated by reference herein in its entirety.

[0002] Described herein are melanocortin subtype-2 receptor (MC2R) antagonists and methods of using the MC2R antagonists in the treatment of conditions, diseases, or disorders that would benefit from modulating melanocortin subtype-2 receptor activity, such as Cushing's disease, congenital adrenal hyperplasia, and ectopic ACTH syndrome. [Background technology]

[0003] Melanocortin receptors form a family of G protein-coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by different melanocortin peptides, adrenocorticotropic hormone (ACTH), and the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH), all of which are proteolytically derived from proopiomelanocortin hormone or POMC. ACTH is a 39-amino acid peptide that is the master regulator of adrenal glucocorticoid synthesis and secretion and has affinity exclusively for MC2R. As a central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted from the pituitary gland in response to stress stimuli and stimulates the synthesis and secretion of cortisol in the adrenal glands. Modulation of MC2R is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulation of melanocortin receptor activity. Summary of the Invention

[0004] Provided herein are methods for the treatment of excess adrenocorticotropic hormone (ACTH) disorders.

[0005] In one aspect, described herein is a method of treating Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof in a human, comprising administering to a human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0006] [ka]

[0007] In some embodiments, the human produces excess ACTH. In some embodiments, the human has a pituitary adenoma or a corticotroph adenoma. In some embodiments, the human has an ectopic ACTH-secreting tumor. In some embodiments, the human has a genetic mutation in the adrenal gland that results in impaired cortisol synthesis. In some embodiments, the human has a mutation in a gene encoding 21β-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase, or a combination thereof. In some embodiments, the human has been or is currently receiving exogenous corticosteroids. In some embodiments, the exogenous corticosteroid is a glucocorticoid.

[0008] In some embodiments, treating Cushing's disease, CAH, EAS, or a combination thereof comprises reducing levels of ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in a human.

[0009] In some embodiments, treating Cushing's disease or EAS, or a combination thereof, comprises reducing the level of cortisol in a human. In some embodiments, treating Cushing's disease or EAS, or a combination thereof, comprises reducing the level of cortisol in blood, serum, saliva, or urine or a human. In some embodiments, treating Cushing's disease or EAS, or a combination thereof, comprises reducing cortisol levels to the average level of a human without Cushing's disease or EAS, or a combination thereof.

[0010] In some embodiments, treating CAH comprises reducing the level of a steroid, an androgen, a steroid precursor, or a combination thereof in a human, hi some embodiments, treating CAH comprises reducing the level of A4, 17-OHP, or a combination thereof in a human.

[0011] In some embodiments, the human with Cushing's disease or ectopic ACTH syndrome (EAS) has a non-pituitary tumor that secretes excessive amounts of ACTH, and the non-pituitary tumor is in the lung, pancreas, thyroid, thymus, intestine, adrenal gland, or paraganglia.

[0012] In some embodiments, treating Cushing's disease or EAS includes reducing the growth of fat pads (collarbone, back of neck, face and trunk), excessive sweating, dilated capillaries, thinning of skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity, menstrual irregularities, or a combination thereof.

[0013] In another aspect, described herein is a method of treating congenital adrenal hyperplasia (CAH) in a human, the method comprising administering to a human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0014] [ka]

[0015] In some embodiments, the human has a genetic mutation that results in impaired cortisol synthesis, ie, the human has a mutation in a gene encoding 21β-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase, or a combination thereof.

[0016] In some embodiments, the CAH is classical CAH. In some embodiments, classical CAH includes salt-wasting CAH or simple male-type CAH.

[0017] In some embodiments, the CAH is non-classical CAH.

[0018] In some embodiments, treating CAH comprises reducing the level of ACTH-stimulated androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in a human. In some embodiments, treating CAH comprises reducing the level of ACTH-stimulated androgens or cortisol precursors in a human. In some embodiments, the androgen comprises androstenedione (A4). In some embodiments, the cortisol precursor comprises 17-hydroxyprogesterone (17-OHP). In some embodiments, treating CAH comprises reducing androgen secretion.

[0019] In some embodiments, treating CAH comprises reducing the incidence of inappropriate gonadal development, hyperandrogenism, and mineralocorticoid replacement. In some embodiments, administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, comprises reducing exogenous glucocorticoid dosage requirements for humans.

[0020] In another aspect, described herein is a method of reducing fat pad growth (collarbone, back of neck, face and trunk), excessive sweating, dilated capillaries, thinning of skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity, menstrual irregularities, or a combination thereof, in a human with congenital adrenal hyperplasia (CAH), comprising administering to a human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0021] [ka]

[0022] In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, comprises reducing the exogenous glucocorticoid dosage requirement for a human with CAH, hi some embodiments, the exogenous glucocorticoid comprises beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or a combination thereof.

[0023] In another aspect, described herein are methods for reducing ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in a human, the methods comprising administering to a human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0024] [ka]

[0025] In some embodiments, the human has Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof.

[0026] In some embodiments, reducing the levels of ACTH-stimulated cortisol, A4, 17-OHP, aldosterone, DHEAS, DHEA, or a combination thereof comprises treating Cushing's disease, CAH, EAS, or a combination thereof.

[0027] In some embodiments of the methods described herein, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is orally administered once daily or twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg of Compound 1. , 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg.

[0028] In another aspect, described herein are methods for treating a disease or condition associated with excess ACTH in a human, the method comprising administering to a human in need thereof a selective non-peptide small molecule melanocortin 2 receptor (MC2R) antagonist, wherein the non-peptide small molecule MC2R antagonist is about 100-fold selective for MC2R over MC1R, MC3R, MC4R, MC5R, or any combination thereof. In some embodiments, administering a selective non-peptide small molecule MC2R antagonist to a human with excess ACTH comprises suppressing or reducing pathological elevations of adrenal steroid hormones mediated by ACTH. In some embodiments, administering a selective non-peptide small molecule MC2R antagonist to a human with excess ACTH comprises suppressing or reducing adrenal cortisol and androgens. In some embodiments, administration of a selective non-peptide small molecule MC2R antagonist to a human with excess ACTH involves suppression or reduction of adrenal-derived cortisol and androgens without substantially affecting mineralocorticoid production.

[0029] In some embodiments, the human has elevated cortisol levels. In some embodiments, the elevated cortisol levels are ACTH-dependent. In some embodiments, the human has a pituitary adenoma or a corticotroph adenoma. In some embodiments, the human has an ectopic ACTH-secreting tumor.

[0030] In some embodiments, treating a disease or condition associated with excess ACTH comprises reducing the levels of ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in a human. In some embodiments, treating a disease or condition associated with excess ACTH comprises reducing the levels of cortisol in a human.

[0031] In some embodiments, the disease or condition associated with excess ACTH comprises Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof.

[0032] In another aspect, described herein are methods for treating Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof in a human, comprising administering to the human a therapeutically effective amount of a selective non-peptide small molecule MC2R antagonist, or a pharmaceutically acceptable salt or solvate thereof, wherein cortisol levels in the human are reduced by at least 10% from baseline. In some embodiments, the cortisol levels in the human are reduced by at least 10% from baseline and maintained at the reduced level for at least 4 hours.

[0033] In some embodiments, the CAH is classical CAH.

[0034] 54. The method of claim 53, wherein the classical CAH comprises salt-wasting CAH or simple androgenetic CAH.

[0035] In some embodiments, the CAH is non-classical CAH.

[0036] In some embodiments of the methods described herein, the selective non-peptide small molecule MC2R antagonist is a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0037] [ka]

[0038] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is orally administered once daily or twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg of Compound 1. , 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg.

[0039] An article of manufacture is provided that includes packaging material, Compound 1, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label indicating that Compound 1, or a pharmaceutically acceptable salt thereof, is used to modulate the activity of a melanocortin receptor (e.g., the melanocortin subtype 2 receptor (MC2R)) or for the treatment, prevention, or amelioration of one or more symptoms of a disease or condition that would benefit from modulation of the activity of a melanocortin receptor (e.g., the melanocortin subtype 2 receptor (MC2R)).

[0040] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0041] [Figure 1] 1 shows the effect of a single dose of Compound 1 on corticosterone levels in male rats following administration of a single dose of ACTH(1-24). [Figure 2] 1 shows the effect of a single dose of Compound 1 on corticosterone levels in female rats following administration of a single dose of ACTH(1-24). [Figure 3] 1 shows the effect of a single dose of Compound 1 on corticosterone levels in rats following administration of repeated doses of ACTH(1-24). [Figure 4] 1 shows a dose-dependent suppression of corticosterone levels in rats given repeated daily administration of Compound 1 followed by continuous administration of ACTH(1-24). [Figure 5] 1 shows the reduction in adrenal weight and adrenal cortical area in rats given repeated daily administration of Compound 1 followed by continuous administration of ACTH(1-24). [Figure 6] 1 shows dose-dependent suppression of corticosterone levels in rats bearing ACTH-secreting AtT-20 cell tumors after repeated daily administration of Compound 1. [Figure 7] Pharmacokinetic results from a single ascending dose (SAD) study of Compound 1 are shown. [Figure 8] 1 shows dose-dependent suppression of basal cortisol production from the adrenal gland from a single ascending dose (SAD) study of Compound 1. [Figure 9] 1 shows dose-dependent suppression of cortisol following a supra-pathophysiological ACTH challenge from a single ascending dose (SAD) study of Compound 1. [Figure 10]1 shows the suppression of basal and ACTH-stimulated cortisol levels in an ACTH stimulation test at a low dose (1 mcg) with Compound 1 treatment. [Figure 11] 1 shows the effect of 80 mg of Compound 1 in a high dose (250 mcg) and low dose (1 mcg) ACTH stimulation test. [Figure 12] Pharmacokinetic results on days 1 and 10 after treatment with a daily dose of 40 mg of Compound 1 for 10 days are shown. [Figure 13] 1 shows the effect of Compound 1 on basal and ACTH-stimulated cortisol levels after 10 days of daily administration of Compound 1. [Figure 14] Over the course of the 10 day study, there is suppression of basal and ACTH-stimulated cortisol secretion at 4 hours post-dose and 24 hours post-dose. [Figure 15] 1 shows suppression of ACTH-stimulated cortisol over a 10-day study using 24-hour circadian sampling to monitor serum cortisol levels. DETAILED DESCRIPTION OF THE INVENTION

[0042] Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide synthesized by the anterior pituitary corticotrophic cells through the proteolytic cleavage of proopiomelanocortin hormone (POMC). ACTH is the primary regulator of adrenal glucocorticoid (GC) synthesis and secretion (cortisol in humans and most other species; corticosterone in rodents). As a central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted from the pituitary gland in response to stressful stimuli and stimulates the synthesis and secretion of cortisol in the adrenal glands. This stimulation is mediated through a highly specific G protein-coupled receptor (GPCR) that is almost uniquely expressed in the adrenal cortex. The receptor is the melanocortin 2 receptor (MC2R), which, together with ACTH, is part of the larger melanocortin system.

[0043] The melanocortin system includes a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R), their natural agonists, the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH), and ACTH, as well as the endogenous melanocortin antagonists aguuti and agouti-related protein (AGRP). Melanocortin receptors (MCRs) have different selectivity for endogenous agonist and antagonist peptides, are expressed in diverse tissues, and perform diverse and discreet physiological functions (Gantz, I. and T. M. Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003).

[0044] It is possible to selectively modulate any one of the MCRs, or a combination thereof, relative to other MCRs. In some embodiments, selectively modulating any one of the MCRs, or a combination thereof, relative to other MCRs, is useful in various clinical applications. In some embodiments, selectively modulating any one of the MCRs, or a combination thereof, relative to other MCRs, reduces undesirable side effects in various clinical applications. In one aspect, the compounds described herein are antagonists of MC2R. In some embodiments, the compounds described herein are selective antagonists of MC2R relative to other MCRs.

[0045] MC2R is a highly selective receptor for ACTH. Although ACTH can activate all five MCRs, at physiological levels, the sensitivity of other receptors is not high enough to activate them, and ACTH selectively activates MC2R. Importantly, other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, have no affinity for MC2R (Gantz, I. and TM Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003). The primary function of MC2R is to stimulate zona fasciculata cells in the adrenal cortex to synthesize and secrete cortisol. MC2R requires the normal secretion and function of the GPCR accessory protein MRAP (melanocortin 2 receptor protein) on the cell surface. MRAP is a small protein with a single transmembrane domain that forms an antiparallel homodimer in a stable complex with MC2R and is required for both the cell surface expression of MC2R and its ability to bind ACTH. MRAP can bind to any of the MCRs and affect their activity, but it is essential only for MC2R activity. Binding of ACTH to the MC2R / MRAP complex on adrenocortical cells is mediated by G S activating ATP to elevate intracellular cAMP levels, which in turn stimulates cortisol synthesis and secretion by regulating multiple steps in the steroidogenic pathway.

[0046] Cushing's disease Cushing's syndrome (CS) is a rare disorder characterized by chronic overexposure to elevated levels of glucocorticoids, particularly cortisol. Clinical signs of Cushing's syndrome include growth of fat pads (on the clavicle, back of the neck, face, and trunk), excessive sweating, dilated capillaries, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and various other metabolic disorders that result in high morbidity. In severe forms, if inadequately controlled, Cushing's syndrome is associated with a high mortality rate. While glucocorticoid excess can be ACTH-independent, resulting from excessive autonomous secretion of cortisol from, for example, hyperfunctioning adrenal adenoma, carcinoma, or steroid abuse, approximately 60–80% of all cases are ACTH-dependent, also known as Cushing's disease (CD).

[0047] Cushing's disease is caused by a pituitary corticotroph tumor that secretes excessive amounts of ACTH, which in turn causes downstream synthesis and excessive secretion of cortisol by the adrenal glands. Cortisol is the body's primary stress hormone, and excessive amounts can cause significantly increased mortality and morbidity. Corticotroph adenomas are small, usually slow-growing, benign tumors that typically become clinically noticeable as a result of the effects of glucocorticoid excess. Cushing's disease is more common in women, usually developing between the ages of 30 and 50. With an estimated diagnosis time of 38 months, it often takes many years to diagnose, and it can be significantly underdiagnosed in the general population because many of its symptoms, such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularities, can be mistakenly attributed to other, more common conditions. Cushing's disease is an orphan disease with a prevalence of approximately 10,000 patients in the United States.

[0048] First-line treatment for Cushing's disease is surgical, involving removal of either the ACTH-secreting tumor in the pituitary gland or, in severe cases, the adrenal gland itself. Because surgery is often unsuccessful, contraindicated, or delayed, pharmacological treatment is necessary for these patients. Adrenal enzyme inhibitors (e.g., metyrapone and ketoconazole) can prevent cortisol synthesis and ameliorate symptoms, but suffer from mechanical side effects as a result of precursor steroid accumulation. For example, metyrapone has been associated with hirsutism in women, and patients must be carefully monitored to avoid adrenal insufficiency, hypokalemia, and hypertension. Ketoconazole often requires incremental dose increases to maintain disease control, but this is ultimately limited by the drug's hepatotoxicity. Additionally, ketoconazole is a potent inhibitor of CYP3A4, one of the most important drug-metabolizing enzymes in the liver, potentially resulting in negative drug interactions. Mifepristone, a potent glucocorticoid receptor antagonist, has been approved for the control of hyperglycemia in Cushing's syndrome, but it is difficult to titrate and has significant side effects due to its potent antiprogestational activity. The recently approved somatostatin analog, pasireotide, inhibits ACTH secretion, but a recently published study found that only 15–26% of patients in a phase 3 trial achieved normalization of urinary free cortisol, while 73% of patients experienced hyperglycemia-related adverse events, likely due to the compound's potent inhibition of insulin secretion.

[0049] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat Cushing's disease. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat glucocorticoid excess in Cushing's disease. In some embodiments, the glucocorticoid excess in Cushing's disease is ACTH-dependent.

[0050] Ectopic ACTH syndrome Ectopic ACTH syndrome (EAS), or ectopic Cushing's syndrome or disease, is a rare disorder caused by a non-pituitary tumor that secretes excessive amounts of ACTH. Often, these tumors occur in the lung. Occasionally, ectopic tumors occur in the pancreas, thyroid, and thymus. Occasionally, ectopic tumors occur in the intestine. Occasionally, ectopic tumors occur on the adrenal gland, such as pheochromocytoma. Occasionally, ectopic tumors occur in paraganglia. Occasionally, ectopic tumors occur in other organs. Occasionally, ectopic tumors are cancerous. The supraphysiological degree of ACTH secretion in EAS can vary, with effects ranging from cushingoid to acute, life-threatening. In some embodiments, the tumor is a small carcinoid tumor occurring anywhere in the lung or gastrointestinal tract.

[0051] Treatment options for EAS are limited, and the initial goal is surgical removal of the tumor, if possible. If surgery is not an option, medication can be used to block cortisol production. In some cases, if the tumor cannot be located and medication does not completely block cortisol production, adrenalectomy is necessary.

[0052] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat ectopic ACTH syndrome.

[0053] Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is characterized by reduced or absent cortisol synthesis due to loss of negative cortisol feedback on the pituitary and hypothalamus, resulting in excess ACTH and corticotropin-releasing hormone. CAH encompasses a range of disorders caused by genetic mutations within the adrenal gland that result in impaired cortisol synthesis.

[0054] In some embodiments, CAH is caused by mutations in 21β-hydroxylase. Different mutations in the gene responsible for 21β-hydroxylase result in different levels of the enzyme, producing a range of effects. CAH due to 21β-hydroxylase deficiency is responsible for 95% of all cases of CAH and is further classified into two subcategories: classic CAH, including salt-wasting and simple male forms, and non-classic CAH. In some cases, classic CAH, if undetected and untreated, can lead to adrenal crisis and death. In other cases, non-classic CAH is milder and may or may not exhibit symptoms. Cortisol deficiency results in hyperstimulation of the adrenal cortex, eliminating negative feedback to the pituitary gland, which leads to excessive ACTH secretion. The resulting adrenal hyperplasia and excessive secretion of other steroids (especially androgens) and steroid precursors can lead to a variety of effects, including improper gonadal development, hyperandrogenism, and life-threatening mineralocorticoid replacement. CAH is an orphan indication with a prevalence of approximately 27,000 patients in the United States.

[0055] In other embodiments, CAH is caused by mutations in 11β-hydroxylase deficiency, 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia, or p450 oxidoreductase deficiency, all of which have different manifestations.

[0056] The current treatment paradigm for CAH consists of lifelong daily glucocorticoid replacement (e.g., hydrocortisone, prednisone, dexamethasone) to balance the inability to synthesize cortisol and alleviate the negative feedback deficit. Mineralocorticoid replacement is also required in approximately two-thirds of patients with classic CAH due to 21β-hydroxylase deficiency. Often, the glucocorticoid dose required to suppress ACTH exceeds physiological replacement, and this excess exogenous glucocorticoid can cause Cushing-like symptoms. Additionally, the inability to accurately administer glucocorticoids can often lead to cycles of over- or undertreatment. Undertreatment can lead to adrenal crisis, and stress doses of glucocorticoids for acute illness are common. Overtreatment can cause CS-like symptoms. Compared to the general population, patients with CAH have twice the risk of fractures and commonly suffer from hypercholesterolemia, insulin resistance, and hypertension. Compared to the general population, life expectancy for patients with CAH is reduced by 7 years, and more than 20% of patients with CAH die from a condition that results in adrenal crisis.

[0057] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat CAH. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat CAH associated with hyperandrogenism. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used to treat Cushingoid symptoms caused by excessive exogenous glucocorticoid administration in the treatment of CAH.

[0058] compound 1 Compound 1 is a potent, oral, non-peptide, small molecule MC2R antagonist (K) that exhibits >2900-fold selectivity over other human melanocortin receptor subtypes. i <10 nM).

[0059] Compound 1 refers to 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperazin-1-yl)-N-((S)-quinuclidin-3-yl)picolinamide, having the chemical structure shown below.

[0060] [ka]

[0061] Compound 1 is also known as N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide.

[0062] Treatment method In certain aspects, disclosed herein are methods for reducing endogenous adrenocorticotropic hormone (ACTH) activity in a human, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In some embodiments, the method comprises reducing the activity of ACTH on the adrenal gland. In some embodiments, the method comprises reducing downstream signaling of ACTH on the adrenal gland. In some embodiments, disclosed herein are methods for reducing endogenous cortisol levels in a human, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In some embodiments, disclosed herein are methods for reducing endogenous adrenal steroid hormone levels in a human, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In another aspect, disclosed herein are methods for inhibiting cortisol secretion from the adrenal gland in a human, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In yet another aspect, disclosed herein are methods of inhibiting adrenal androgen secretion and cortisol precursor production in a human, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In some embodiments, the androgen is androstenedione (A4). In some embodiments, the cortisol precursor is 17-hydroxyprogesterone (17-OHP). In some embodiments, the human has a disorder associated with excess adrenocorticotropic hormone (ACTH). In some embodiments, the human has Cushing's disease. In some embodiments, the human has CAH. In some embodiments, the human has EAS.

[0063] In certain aspects, disclosed herein are methods for reducing cortisol levels in a human having a disorder associated with excess adrenocorticotropic hormone (ACTH), comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In certain embodiments, the method comprises reducing endogenous cortisol levels. In other embodiments, the method comprises reducing ACTH-stimulated cortisol levels. In some embodiments, the disorder associated with excess ACTH is Cushing's disease. In some embodiments, the disorder associated with excess ACTH is CAH. In some embodiments, the disorder associated with excess ACTH is EAS.

[0064] In certain aspects, disclosed herein are methods for reducing cortisol levels in a human with Cushing's disease, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In certain aspects, disclosed herein are methods for reducing cortisol levels in a human with CAH, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In certain aspects, disclosed herein are methods for reducing cortisol levels in a human with EAS, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In certain aspects, disclosed herein are methods for reducing cortisol levels in a human with CAH and Cushing's-like symptoms, comprising administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof. In certain embodiments, the method comprises reducing endogenous cortisol levels. In other embodiments, the method comprises reducing ACTH-stimulated cortisol levels.

[0065] In some embodiments, the methods disclosed herein include methods of treating a disease associated with excess ACTH. In some embodiments, the disease includes excess cortisol levels. In some embodiments, the treatment includes reducing cortisol levels. In some embodiments, the treatment includes reducing endogenous cortisol levels. In some embodiments, the treatment includes reducing ACTH-stimulated cortisol levels. In some embodiments, the disease associated with excess ACTH is Cushing's disease. In some embodiments, the disease associated with excess ACTH is CAH. In some embodiments, the disease associated with excess ACTH is EAS.

[0066] In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises treating one or more symptoms of Cushing's syndrome. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing fat pad growth (collarbone, back of neck, face, and trunk), excessive sweating, dilated capillaries, thinning of skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity, menstrual irregularities, or a combination thereof. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing fat pad growth (collarbone, back of neck, face, and trunk). In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing excessive sweating. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing dilated capillaries. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing thinning of skin. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing muscle weakness. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing hirsutism. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing depression / anxiety. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing hypertension. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing osteoporosis. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing insulin resistance.

[0067] In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing hyperglycemia. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing heart disease. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing lethargy. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing obesity. In some embodiments, treating Cushing's syndrome, including Cushing's disease, comprises reducing menstrual irregularities.

[0068] In some embodiments, treating CAH comprises reducing inappropriate gonadal development, hyperandrogenism, and mineralocorticoid replacement. In some embodiments, treating CAH comprises reducing inappropriate gonadal development. In some embodiments, treating CAH comprises reducing hyperandrogenism. In some embodiments, treating CAH comprises reducing mineralocorticoid replacement.

[0069] In some embodiments, the methods described herein include reducing the level of at least one metabolite. In some embodiments, the metabolite is an ACTH-stimulated metabolite. In some embodiments, the metabolite includes cortisol, A4, 17-OHP, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof. In some embodiments, the method includes reducing the level of endogenous cortisol. In some embodiments, the method includes reducing ACTH-stimulated cortisol, A4, 17-OHP, aldosterone, DHEAS, DHEA, or a combination thereof. In some embodiments, the metabolite is reduced compared to the level of the metabolite in the subject before treatment. In some embodiments, the metabolite is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more than 50%.

[0070] In some embodiments, the methods described herein include reducing cortisol levels. In some embodiments, the methods include reducing endogenous cortisol levels. In some embodiments, endogenous cortisol levels are reduced in blood, serum, saliva, or urine. In some embodiments, the methods include reducing ACTH-stimulated cortisol. In some embodiments, ACTH-stimulated cortisol levels are reduced in blood, serum, saliva, or urine. In some embodiments, blood cortisol levels are reduced. In some embodiments, serum cortisol levels are reduced. In some embodiments, saliva levels are reduced. In some embodiments, urinary free cortisol (UFC) levels are reduced. In some embodiments, cortisol levels are reduced as determined by an ACTH stimulation test. In some embodiments, cortisol levels are reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more than 50%. In some embodiments, the level of cortisol in blood, serum, saliva, or urine is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more than 50%. In some embodiments, the level of cortisol is reduced compared to the level of cortisol before treatment. In some embodiments, the level of cortisol is reduced to the level of a human not having one of the disorders described herein. That is, in some embodiments, the level of cortisol is restored to normal in a human.

[0071] subject In some embodiments, the subject is a human.

[0072] In some embodiments, the subject has a disease associated with excess ACTH. In some embodiments, the subject has Cushing's disease. In some embodiments, the subject has CAH. In some embodiments, the subject has EAS. In some embodiments, the subject has Cushing-like symptoms caused by excessive exogenous glucocorticoid administration in the treatment of CAH.

[0073] In some embodiments, the human has excess cortisol. In some embodiments, the human has elevated cortisol levels. Optionally, the human without elevated cortisol levels has a blood cortisol level of about 10-20 mcg / dL or a cortisol level of 50-100 mcg / day in a 24-hour urine cortisol test. In some embodiments, the human has a blood cortisol level of about 20 mcg / dL, 25 mcg / dL, 30 mcg / dL, or higher. In some embodiments, the human has a 24-hour urine cortisol level of about 50 mcg / day, 100 mcg / day, 150 mcg / day, 200 mcg / day, or higher in a 24-hour urine cortisol test.

[0074] In some embodiments, the human has a 24-hour urinary cortisol excretion that is higher than the upper limit of normal (ULN) for humans. In some embodiments, the human has a 24-hour urinary cortisol excretion that is at least 1.5, 2.0, 2.5, or more times the ULN. In some embodiments, the ULN for 24-hour urinary cortisol excretion is about 50-55 mcg / day.

[0075] In some embodiments, the human has midnight salivary cortisol levels that are higher than the ULN for the human. In some embodiments, the human has midnight salivary cortisol levels that are at least 1.5, 2.0, 2.5, or more times the ULN. In some embodiments, the ULN for midnight salivary cortisol levels is about 100 ng / dL.

[0076] In some embodiments, the human has elevated serum cortisol in a low-dose dexamethasone suppression test, hi some embodiments, the human has a serum cortisol level of 1.8 mcg / dL or greater the morning after an overnight dose of 1 mg dexamethasone.

[0077] In some embodiments, the human has excess cortisol that is ACTH-dependent. In some embodiments, the human has excess ACTH. In some cases, the human does not have elevated ACTH levels, but has blood levels of about 10-50 pg / mL. In some embodiments, the human has blood levels of ACTH that are about 50 pg / mL, 75 pg / mL, 100 pg / mL, or higher.

[0078] In some embodiments, the human has been or is currently being administered an exogenous corticosteroid. In some embodiments, the human has been or is currently being administered an exogenous corticosteroid, and the exogenous corticosteroid is a glucocorticoid. In some embodiments, the human has been or is currently being administered an exogenous corticosteroid, and the exogenous corticosteroid is an oral, injectable, or inhaled corticosteroid. In some embodiments, the human has been exposed to an exogenous glucocorticoid. In some embodiments, the human has been exposed to an exogenous glucocorticoid for a sustained period of time to treat an acute or chronic condition in the human. In some embodiments, the exogenous glucocorticoid is an oral, injectable, or inhaled corticosteroid. In some embodiments, the exogenous glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or the like. In some embodiments, the exogenous glucocorticoid is used to treat an inflammatory disease, such as rheumatoid arthritis, lupus, or asthma, joint pain, bursitis, back pain, or a skin disease, such as eczema, in a human. In some embodiments, the human has CAH and has been exposed to an exogenous glucocorticoid. In some such embodiments, the human with CAH exhibits Cushingoid symptoms.

[0079] In some embodiments, the human produces excess ACTH. In some embodiments, the human has a pituitary tumor (pituitary adenoma) or a corticotroph adenoma. In some embodiments, the pituitary adenoma or corticotroph adenoma is benign. In other embodiments, the human has an ectopic ACTH-secreting tumor. In other embodiments, the human has an ACTH-secreting tumor in an organ that does not normally produce ACTH. In some embodiments, the ACTH-secreting tumor is in the lung, pancreas, thyroid, thymus, intestine, adrenal gland, or paraganglia. In some embodiments, the ACTH-secreting tumor is cancerous. In some embodiments, the ACTH-secreting tumor is benign.

[0080] In some embodiments, the human has a mutation in a genetic locus that affects cortisol synthesis. The most common mutation (approximately 95%) occurs in the gene encoding 21β-hydroxylase, resulting in 21β-hydroxylase deficiency. Rare causes include genetic mutations in genes encoding 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase. In some embodiments, the human has a mutation in a gene encoding 21β-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase, or a combination thereof.

[0081] Dosage and Administration In one embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is used in the preparation of a medicament for the treatment of a disease associated with excess ACTH. A method for treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least Compound 1, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0082] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0083] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. When used in patients, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to a subject who has experienced at least one symptom of a previously treated disease and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0084] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the entire life of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0085] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0086] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0087] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to a human. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to a human on a continuous dosing schedule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to a human on a continuous daily dosing schedule.

[0088] The term "continuous dosing schedule" refers to the periodic administration of a particular therapeutic agent. In some embodiments, a continuous dosing schedule refers to the periodic administration of a particular therapeutic agent without any drug-free period from the particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent in cycles. In some other embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent in a cycle of drug administration followed by a drug-free period from the particular therapeutic agent (e.g., a washout period or other such period during which the drug is not administered). For example, in some embodiments, the therapeutic agent is administered once daily, twice daily, three times daily, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, seven times weekly, every other day, every third day, every fourth day, daily for one week followed by one week of no therapeutic agent, daily for two weeks followed by one or two weeks of no therapeutic agent, daily for three weeks followed by one, two, or three weeks of no therapeutic agent, daily for four weeks followed by one, two, three, or four weeks of no therapeutic agent, weekly administration followed by one week of no therapeutic agent, or biweekly administration followed by two weeks of no therapeutic agent. In some embodiments, the daily administration is once daily. In some embodiments, the daily administration is twice daily. In some embodiments, the daily administration is three times daily. In some embodiments, the daily administration is more than three times daily.

[0089] The term "continuous daily dosing schedule" refers to daily administration of a particular therapeutic agent at approximately the same time each day. In some embodiments, the daily administration is once daily. In some embodiments, the daily administration is twice daily. In some embodiments, the daily administration is three times daily. In some embodiments, the daily administration is more than three times daily.

[0090] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered once daily.

[0091] In certain embodiments where no improvement in the state of the disease or condition in humans is observed, the daily dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is increased. In some embodiments, a once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, a three-times-daily dosing schedule is employed to increase the amount of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, administered. In some embodiments, the dosing frequency is increased to provide sustained or more regular exposure to the ACTH antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the dosing frequency is increased to provide more regularly repeated high Cmax levels and / or to provide sustained or more regular exposure to the ACTH antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof).

[0092] Any of the foregoing aspects include further embodiments comprising a single administration of an effective amount of an ACTH antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof), including further embodiments in which the ACTH antagonist is administered (i) once daily, or (ii) multiple times daily.

[0093] Any of the foregoing aspects include further embodiments that include multiple administrations of an effective amount of an ACTH antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof), including further embodiments in which (i) the ACTH antagonist is administered continuously or intermittently, such as in a single dose; (ii) the time between multiple doses is every 6 hours; (iii) the ACTH antagonist is administered to the mammal every 8 hours; (iv) the ACTH antagonist is administered to the mammal every 12 hours; and (v) the ACTH antagonist is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the ACTH antagonist is temporarily suspended or the dose of the ACTH antagonist administered is temporarily reduced, and at the end of the drug holiday, administration of the ACTH antagonist is resumed. In one embodiment, the length of the drug holiday varies from two days to one year.

[0094] In general, however, doses of Compound 1 used in adult human treatment typically range from 0.01 mg to 500 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more sub-doses per day.

[0095] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 250 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1.

[0096] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg of Compound 1. , 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 40 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 80 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 120 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 160 mg of Compound 1.

[0097] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 It is administered in doses of 45mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg.

[0098] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg of Compound 1. , 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg or less.

[0099] In one embodiment, a suitable daily dosage for Compound 1, or a pharmaceutically acceptable salt or solvate thereof, described herein is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active agent in a dosage form is lower or higher than the ranges set forth herein, depending on several variables related to the particular treatment regime. In various embodiments, the daily dose and unit dose will vary depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0100] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD. 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit dose amounts for use in subjects, including humans. In some embodiments, the daily dosage of the compounds described herein is sufficient to achieve an ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dose amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0101] Biomarker detection-based therapy In some embodiments, administration of a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is based on the patient's circulating cortisol level, androstenedione (A4) level, 17-hydroxyprogesterone (17-OHP) level, aldosterone level, dehydroepiandrosterone sulfate (DHEAS) level, dehydroepiandrosterone (DHEA) level, or a combination thereof.

[0102] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered via a titration schedule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered via a titration schedule to minimize adverse events associated with the administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, titration with Compound 1, or a pharmaceutically acceptable salt or solvate thereof, allows the subject to tolerate Compound 1, or a pharmaceutically acceptable salt or solvate thereof, minimize adverse events associated with the administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, maximize the likelihood that an optimized dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, will be administered and tolerated by the subject, or a combination thereof. In some embodiments, titration comprises one or more cycles of dose escalation (i.e., upward titration), dose reduction (i.e., downward titration), or a combination thereof. In some embodiments, titration comprises upward titration.

[0103] As used herein, a subject is said to "tolerate" a dose of a compound if administration of that dose to that subject does not result in an unacceptable adverse event or an unacceptable combination of adverse events. Those skilled in the art will understand that tolerance is a subjective measure, and what may be tolerable to one patient may not be tolerable to a different patient.

[0104] As used herein, an "adverse event" is an untoward medical occurrence associated with treatment with Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0105] As used herein, an "optimized dose" refers to a therapeutic dose optimized for the needs of a particular subject, and is the highest dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, that elicits the biological or pharmaceutical response desired and tolerable in the subject, as determined by the subject, optionally in consultation with the subject's healthcare professional, corresponding to the highest dose of Compound 1. In some embodiments, once an "optimized dose" is determined, the optimized dose is administered to the subject for as long as treatment is required (i.e., the optimized dose is a maintenance dose).

[0106] In some embodiments, the titration schedule for Cushing's disease and / or EAS is based on the rate of cortisol change, individual tolerance, and improvement of disease signs and symptoms. In some embodiments, the titration schedule for Cushing's disease and / or EAS is based on urinary free cortisol (UFC) levels. In some embodiments, the titration schedule for Cushing's disease and / or EAS is based on the rate of change of urinary free cortisol (UFC) levels.

[0107] As used herein, "up-titrating" a compound refers to increasing the amount of the compound until the subject no longer tolerates the increased dose. Up-titrating can be accomplished in one or more dose increments, which can be the same or different. In some embodiments, the method comprises administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, at an initial dose once daily for an initial period, followed by up-titrating to a higher dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily thereafter. In some embodiments, the initial period comprises 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0108] In some embodiments, the titration method comprises administering an initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once or twice daily for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by up-titrating to a higher dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once or twice daily thereafter. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0109] In some embodiments, the titration method comprises administering an initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by up-titrating to a higher dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily thereafter. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0110] In some embodiments, the method of titration comprises an upward titration, or a downward titration, followed by an optional further upward titration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0111] In some embodiments, the titration schedule includes administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, at an initial dose for about one week, and increasing the dose by an amount equal to a first increment, provided that the patient tolerates the initial dose, or decreasing the dose by an amount equal to the first increment, provided that the patient does not tolerate the initial dose.

[0112] In some embodiments, the titration schedule further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about one week or two weeks, and further increasing the dose by an amount equal to a second increment, provided the patient tolerates the increased dose; or administering Compound 1 or a pharmaceutically acceptable salt thereof at a decreased dose for about one week, and optionally increasing the dose by an amount equal to a second increment, provided the patient tolerates the decreased dose. In some embodiments, the first increment is the same as the second increment. In some embodiments, the first increment and the second increment are different.

[0113] In some embodiments of the titration scheme, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is adjusted every week, every two weeks, every three weeks, or every four weeks.

[0114] In some embodiments of the titration scheme, if the human has a 24-hour urinary free cortisol (UFC) level above the ULN, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is increased by an incremental value.

[0115] In some embodiments of the titration scheme, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is decreased if UFC levels fall below the target range and / or if there is a rapid decrease in cortisol levels.

[0116] In some embodiments, the optimized dose is achieved when the 24-hour urinary free cortisol (UFC) level is no longer greater than the ULN, the 24-hour urinary free cortisol (UFC) level does not change substantially in response to the treatment, or a combination thereof.

[0117] In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, corresponds to about 1 mg to about 300 mg of Compound 1. In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, corresponds to about 1 mg to about 200 mg of Compound 1. In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, corresponds to about 1 mg to about 100 mg of Compound 1. In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, corresponds to about 1 mg to about 50 mg of Compound 1.

[0118] In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 15 ... It is administered in an amount equivalent to 5 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg.

[0119] In some embodiments, the first increment is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about This is equivalent to 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0120] In some embodiments, the second increment is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about This is equivalent to 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0121] In some embodiments, the titration schedule is repeated until an optimized dose is achieved, which provides therapeutic efficacy while minimizing side effects from ACTH antagonist therapy.

[0122] In some embodiments, the optimized dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg.

[0123] In some embodiments, the optimized dose is tapered if UFC levels fall below the target range and / or if there is a rapid decrease in cortisol levels.

[0124] Combination therapy In certain instances, it will be appropriate to administer at least Compound 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more other therapeutic agents.

[0125] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (including a treatment regimen) that also has a therapeutic benefit.

[0126] In one particular embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is co-administered with a second therapeutic agent, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0127] In one specific embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is co-administered with a second therapeutic agent, wherein the second therapeutic agent is a glucocorticoid, a mineralocorticoid, or a combination thereof. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, reduces the exogenous glucocorticoid dosage requirement for humans. Examples of glucocorticoids contemplated for co-administration include, but are not limited to, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and the like. Examples of mineralocorticoids contemplated for co-administration include, but are not limited to, fludrocortisone, and the like.

[0128] In some embodiments for the treatment of Cushing's disease or EAS, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is co-administered with a second therapeutic agent, wherein the second therapeutic agent is a glucocorticoid (i.e., "block and replace" therapy). In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etamethasoneb, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone. In some embodiments for the treatment of Cushing's disease or EAS, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is co-administered with a low-dose glucocorticoid. In some embodiments, the low-dose glucocorticoid comprises a prednisone equivalent of 20 mg / day or less. In some embodiments, the low-dose glucocorticoid comprises a prednisone equivalent of 15 mg / day or less. In some embodiments, the low dose glucocorticoid comprises a prednisone equivalent of 10 mg / day or less, hi some embodiments, the low dose glucocorticoid comprises a prednisone equivalent of 5 mg / day or less.

[0129] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0130] In the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with or sequentially with the one or more other therapeutic agents.

[0131] In combination therapy, the multiple therapeutic agents (one of which is a compound, or a pharmaceutically acceptable salt or solvate thereof) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form, or in multiple forms (e.g., as a single tablet or as two separate tablets).

[0132] Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and combination therapies may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for as long as necessary to treat the disease. In some embodiments, the length of treatment required varies, and the length of treatment is adjusted to suit the specific needs of each subject.

[0133] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into pharmaceutical preparations. The appropriate formulation depends on the selected route of administration. Summary descriptions of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0134] In some embodiments, the compounds described herein are administered alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. The compounds and compositions described herein can be administered by any method that allows delivery of the compound to the site of action. These methods include oral administration.

[0135] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, hi some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0136] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide sustained or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0137] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0138] Certain terms Unless otherwise stated, the following terms used in this application have the definitions set forth below. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0139] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a sample" includes a plurality of samples, including mixtures thereof.

[0140] As used herein, the term "about" refers to plus or minus 10% of the number. The term "about" a range refers to the range minus 10% of its minimum value and minus 10% of its maximum value.

[0141] The terms "determining," "measuring," "assessing," "evaluating," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present (e.g., detecting). These terms can include quantitative, qualitative, or quantitative and qualitative determinations. Assessment can be relative or absolute. "Detecting the presence of" can include determining the amount of something present in addition to determining whether it is present or absent, depending on the context.

[0142] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it does not have lasting adverse effects on the general health of the subject being treated.

[0143] The term "modulate," as used herein, means to directly or indirectly interact with the activity of a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0144] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0145] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0146] Terms such as "co-administration," as used herein, are intended to encompass administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0147] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound administered, which relieves to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein required to result in a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0148] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0149] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both the active ingredients, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the adjuvant are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the adjuvant are administered to a patient simultaneously, concurrently, or sequentially as separate entities without specific intervening time restrictions, such that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0150] The terms "article of manufacture" and "kit" are used synonymously.

[0151] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs; and the like. In one aspect, the mammal is a human.

[0152] The terms "treat," "treating," or "treatment," as used herein, include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or halting the symptoms of a disease or condition, either prophylactically and / or therapeutically.

[0153] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0154] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [Example]

[0155] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0156] Example 1: Melanocortin Receptor (MCR) Assay Inhibition of ACTH binding: Crude membrane fractions are prepared from CellSensor CRE-bla CHO-K1 cells stably expressing functional hMC2 receptors (ThermoFisher #K1483). Culture cells in growth medium [GlutaMax DMEM (Gibco #10569-010) supplemented with 10% dialyzed fetal bovine serum (Gemini Bio-Products #100-108), 0.1 mM non-essential amino acids (Gibco #11140-050), 100 U / mL penicillin, 100 μg / mL streptomycin, 2 mM L-glutamine (Gemini Bio-Products #400-110), 5 μg / mL blastidine (GoldBio #B-800-100), 100 μg / mL zeocin (Invitogen #R25005), and 600 μg / mL hygromycin B (GoldBio #31282-04-9)] until 85-100% confluency. Cells were harvested and washed in Dulbecco's phosphate-buffered saline (Corning #21-031-CV). Cell pellets were reconstituted in membrane preparation buffer [20 mM HEPES (Biopioneer #C0113), 6 mM MgCl2 (Sigma #M8266), and 1 mM EDTA (JT Baker #4040-01), protease inhibitor tablets (Pierce #A32963); pH 7.4] and homogenized using a Dounce homogenizer. Membrane fractions were separated from cell debris, collected in membrane preparation buffer, flash-frozen in liquid nitrogen, and stored at -80°C.

[0157] Inhibition of binding to the human MC2R receptor was measured using radiolabeled [ 125 I]-TYR 23]-ACTH(1-39) ligand (PerkinElmer #NEX083, custom synthesis) was used as a probe ligand for the receptor. Briefly, membranes from cells expressing human MC2R were incubated with SPA beads (PerkinElmer #RPNQ0001) in binding assay buffer [50 mM HEPES (Biopioneer #C0113), 5 mM MgCl2 (Sigma #M8266), 1 mM CaCl2 (Fisher Scientific #BP510), 0.2% BSA (Fisher Scientific #BP1600), and protease inhibitors (Pierce #A32963); pH 7.4]. The membranes bound to the SPA beads were treated with various dilutions of compound (final concentrations typically 0-10,000 nM) and 0.2 nM radiolabeled ligand in a 96-well Isoplate (PerkinElmer #6005040) at room temperature for 90 minutes. Radioactive signals were detected using a MicroBetaTriLux1450 LSC (PerkinElmer). i All data manipulations to determine values ​​were performed using GraphPad v8 (GraphPad, San Diego CA).

[0158] Compound 1 potently inhibited human MC2R (hMC2R)-mediated cAMP production, with an equilibrium inhibition constant (K i The half-maximal inhibitory concentrations (IC) in the binding assays were <10 nM. Selectivity against other human MCR subtypes was assessed using commercially available MC1R, MC3R, MC4R, and MC5R membrane binding assays. 50 ) were determined to be greater than the highest concentrations tested, or >10,000 nM, >1000 nM, >10,000 nM, and >1000 nM for MC1R, MC3R, MC4R, and MC5R, respectively. Compound 1 exhibits greater than 2900-fold selectivity for MC2R compared to other human MCRs.

[0159] Example 2: Off-target selectivity panel Compound 1 was tested for evaluation in the SafetyScreen™ panel of assays from Eurofins Panlabs Discovery Services Taiwan, Ltd., which includes selectivity assays across 87 targets, including G protein-coupled receptors, nuclear receptors, other cell surface receptors, ion channels, enzymes, and transporters. Compound 1 was tested at a single concentration (10 μM) and showed little activity across the panel. Its activity at the serotonin 5-hydroxytryptamine 1B receptor (5-HT 1B ), calcium channel L-type (phenylalkylamines), and sodium channel (site 2) only showed greater than 70% inhibition / activity at this concentration.

[0160] 5-HT in functional agonist and antagonist modes 1B Subsequent dose response of Compound 1 to the receptor showed that Compound 1 had agonist activity (no signal up to 3000 nM) and weak antagonist activity (IC 50 It was determined that the 5-HT 1B The selectivity of Compound 1 for hMC2R over hMC2R is greater than 2200-fold.

[0161] Example 3: Suppression of ACTH-induced corticosterone The pharmacodynamic (PD) effects of Compound 1 were investigated in rats by assessing the suppression of the corticosterone (cortisol in humans) response induced by administration of ACTH.

[0162] Single oral dose ACTH challenge test: The ability of a single oral dose of Compound 1 to suppress corticosterone levels over a 2-hour period in response to an ACTH challenge test was assessed in male and female rats. Acute IV administration of 1 μg / kg ACTH(1-24) induced a robust increase in plasma corticosterone levels compared to baseline in male and female rats. Oral administration of Compound 1 dose-dependently suppressed ACTH-stimulated corticosterone secretion.

[0163] Statistically significant suppression of corticosterone was observed at ≥3 mg / kg Compound 1 in male rats (62% and 78% suppression at 3 and 10 mg / kg, respectively; Figure 1) and at ≥1 mg / kg Compound 1 in female rats (51%, 71%, and 88% suppression at 1, 3, and 10 mg / kg, respectively; Figure 2) compared to vehicle-treated rats. The minimally effective dose of orally administered Compound 1, as determined in the 1 μg / kg ACTH stimulation acute assay, was 3 mg / kg in male rats, with a C of 149 ng / mL. max and the last measurable concentration of 1400 ng·hr / mL (AUC 0-t ) was associated with an AUC of up to

[0164] Effect of a single oral dose with repeated ACTH challenges: The ability of a single dose of Compound 1 to suppress corticosterone after repeated ACTH(1–24) (1 μg / kg) challenges was assessed to determine the reproducibility of ACTH-stimulated corticosterone responses and the time required to restore corticosterone responses to vehicle levels.

[0165] As shown in Figure 3, after each ACTH stimulation test (1, 4, 24, and 48 hours after administration of Compound 1), corticosterone reproducibly increased from baseline (<100 ng / mL) to >350 ng / mL in vehicle-treated rats. Compound 1 suppressed ACTH-stimulated corticosterone at 1 hour (44% and 88% at 3 and 30 mg / kg, respectively) and 4 hours (36% and 84% at 3 and 30 mg / kg, respectively) after oral administration compared with vehicle treatment. ACTH-stimulated corticosterone returned to normal vehicle levels at 24 and 48 hours after a single oral dose of Compound 1 at 3 or 30 mg / kg.

[0166] Example 4: Suppression of ACTH-induced corticosterone in animal disease models Compound 1 was evaluated in disease models of excess ACTH and hypercortisolism in rats and mice.

[0167] Continuous pump administration of ACTH: Exogenous ACTH(1–24) (100 μg / kg / day) was administered to male rats via subcutaneously implanted osmotic pumps. Compound 1 was administered orally daily for 7 days to assess its ability to suppress corticosterone.

[0168] Compound 1 administered at 10 mg / kg / day or more dose-dependently suppressed corticosterone levels measured 1 hour after administration on days 1 and 7 (FIG. 4).

[0169] Additionally, Compound 1 ameliorated adrenal hypertrophy by alleviating adrenal weight and adrenal cortical area in rats administered 10 and 30 mg / kg / day compared to vehicle treatment (Figure 5).

[0170] ACTH-secreting mouse pituitary cell tumor model: Compound 1 was evaluated for its ability to suppress corticosterone in a mouse model of ACTH excess by daily oral administration for 14 days.

[0171] Briefly, female Balb / c nude mice were implanted subcutaneously with AtT-20 corticotroph tumor cells (3 million cells / injection / animal) in the hind flank on day 0. The tumor-free (NT) control group was injected with medium only. When tumors became palpable on day 21, mice were randomized into groups based on body weight and 0, 15, 30, or 100 mg / kg / day of Compound 1. Compound 1 was administered orally for 14 days (days 21-34).

[0172] Daily oral administration of Compound 1 had no significant effect on tumor volume or body weight over the course of the experiment. On day 34, mice subcutaneously implanted with ACTH-secreting AtT-20 corticotroph tumor cells exhibited a 3.8-fold increase in plasma ACTH and a 1.7-fold increase in plasma corticosterone levels compared with mice receiving sham injections of medium alone (Figure 6). Repeated oral administration of Compound 1 at 15 mg / kg / day or higher doses dose-dependently suppressed plasma corticosterone by 73%, 88%, and 92% at 15, 30, and 100 mg / kg / day, respectively, compared with vehicle treatment in mice bearing ACTH-secreting AtT-20 cell tumors, as assessed 2 hours after administration on the final day of administration. A 2.4-fold increase in ACTH levels was observed with Compound 1 at 100 mg / kg / day compared with vehicle treatment.

[0173] Example 5: Clinical Trial to Evaluate the Effect of Compound 1 on Adrenocorticotropic Hormone (ACTH) in Humans Non-limiting examples of clinical trials of ACTH antagonists in humans are described below.

[0174] the purpose: This Phase 1, first-in-human, double-blind, randomized, placebo-controlled study will evaluate the safety of Compound 1 in healthy volunteers and the relationship between exposure and pharmacodynamic (PD) parameters, including ACTH-stimulated and endogenous cortisol secretion measured in blood, saliva, and urine. Results will be used to inform endpoints and other parameters in future follow-on studies in patients with Cushing's disease (CD) or other disorders of excess adrenocorticotropic hormone (ACTH), including congenital adrenal hyperplasia (CAH) and ectopic ACTH syndrome (EAS).

[0175] intervention: Screening period: within 28 days

[0176] Treatment duration: 1 day / single dose for SAD, 10 days for MAD

[0177] Evaluation and observation period: 6 days for SAD and 17 days for MAD

[0178] Follow-up period: At least 7 days after the last dose of study drug (planned: Day 8 / SAD and Day 20 / MAD)

[0179] SAD / Part 1: Ascending single dose, randomized, placebo-controlled, double-blind; 5 planned cohorts and a maximum of 8 total cohorts, n=64. In each cohort, 6 subjects will receive Compound 1 and 2 subjects will receive placebo. Dose will escalate from 10 mg to ≤250 mg in Cohort 1.

[0180] MAD / Part 2: Multiple ascending dose, randomized, placebo-controlled, double-blind; 2 planned cohorts and up to 4 total cohorts (n=36). In each cohort, 6 subjects will receive Compound 1 and 3 subjects will receive placebo. Doses will not exceed those in the SAD.

[0181] Inclusion criteria: Healthy male and female subjects aged 18 to 55 years at the time of screening. Women must be at least 12 months postmenopausal or surgically sterile, or agree to use a stable, licensed, highly effective method of contraception from screening until at least 30 days after the last dose of study drug. Men must be surgically sterile or abstinent, or agree to use spermicide-coated condoms if sexually active with a female partner of childbearing potential from screening until at least 30 days after the last dose of study drug. The female partner must also use a highly effective form of contraception during this same period. Male subjects must also agree not to donate sperm during the study and until at least 90 days after the last dose of study drug.

[0182] Peak ACTH-stimulated serum cortisol of 18 μg / dL or greater at 30 or 60 minutes at screening.

[0183] Exclusion criteria: Subjects will be excluded based on the following criteria: pregnant or lactating women; prior treatment with Compound 1; use of topical, nasal, inhaled, or oral corticosteroids within 3 days or 5 half-lives, whichever is longer, prior to the randomization date, or if expected to be required during the study; use of prohibited prescription or non-prescription drugs and / or non-prescription / alternative medications within 7 days prior to screening and no intention to discontinue use of these substances during the study (unless otherwise specified); use of drugs that are strong inducers of cytochrome P450 CYP3A4 within 30 days prior to screening for this study, or use of strong inhibitors of CYP3A4 within 14 days prior to screening; use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer, prior to screening; any condition that, in the opinion of the investigator, may compromise the subject's adequate participation in this study.

[0184] Outcome measures: To evaluate the safety and tolerability of single and multiple doses of Compound 1.

[0185] To evaluate single- and multiple-dose PK of Compound 1.

[0186] To evaluate the PD effects of Compound 1, including suppression of ACTH-stimulated serum cortisol and adrenal androgen production, morning serum cortisol, and adrenal androgen production.

[0187] During the MAD phase, 24-hour urinary free cortisol (UFC) will be assessed to collect initial dose-response data that can be used to confirm dosing for subsequent studies of Cushing's disease (CD) and ectopic ACTH syndrome (EAS).

[0188] Additionally, the effects of Compound 1 on adrenal androgen and cortisol precursor secretion (including A4 and 17-OHP, respectively) were assessed in both SAD and MAD, which can be used to support dosing for subsequent studies of congenital adrenal hyperplasia (CAH).

[0189] Elevated ACTH(1–39) in potential patient populations is measured at designated time points to gain understanding of drug effects on endogenous ACTH.

[0190] ACTH stimulation test The ACTH stimulation test will be administered on multiple study days throughout both phases of this study. This test is considered the diagnostic "gold standard" for the diagnosis of adrenal insufficiency due to its frequency of use and validation.

[0191] Initially, an ACTH stimulation test is performed at screening to assess the hypothalamic pituitary-adrenal (HPA) axis as a safety factor, i.e., to ensure that subjects have adequate adrenal function (as assessed by ACTH-stimulated peak cortisol secretion) before entering the study. During the study, additional ACTH stimulation tests are performed to produce an exogenous elevation of ACTH and a consequent elevation of cortisol and androgens.

[0192] ACTH stimulation tests are performed during fasting. For PD analysis, blood samples are collected for measurement of serum cortisol, A4, 17-OHP, aldosterone, and DHEA. The procedure is outlined as follows: In "high-dose" studies, each subject receives an IV 250 μg dose (for subjects over 37 lbs) of cosyntropin (ACTH(1-24)) at the beginning of each study; in "low-dose" studies, 1 mcg is administered instead. At time 0 (± 5 min) 2 hours after study drug administration, a blood sample is collected. Within 5 minutes, a cosyntropin IV infusion is administered over 2 minutes. At time 30 min (± 5 min), a blood sample is collected. At time 60 min (± 5 min), a blood sample is collected.

[0193] SAD blood biomarkers Endocrine biomarkers will be assessed throughout the study.

[0194] Morning biomarkers: Starting on day -1 and continuing until EOS (or ET), fasting, pre-dose blood samples are collected within 15 minutes prior to dosing (approximately 0800 hours) for serum cortisol, A4, 17-OHP, aldosterone, ACTH (1 39), renin, and DHEAS. On days when ACTH stimulation tests are performed, these tests are performed approximately 2 hours after study drug administration. Prior to cosyntropin administration, blood samples are collected 2 hours (±15 minutes) after dosing for cortisol, A4, 17-OHP, aldosterone, and DHEA. Cosyntropin is then administered to define time 0 for the ACTH stimulation test. 2.5 hours (±15 minutes) after dosing / 30 minutes after cosyntropin, blood samples are collected for cortisol measurement. Blood samples are collected 3 hours (±15 minutes) post-dose / 60 minutes post-cosyntropin for measurement of cortisol, A4, 17-OHP, aldosterone, and DHEA.

[0195] Intermediate day biomarkers: Fasting blood samples are collected for measurement of serum cortisol 4 hours (±15 minutes) post-dose (approximately 1200 hours) on days -1, 1, and 2. On days when ACTH stimulation testing is performed, this collection is 120 minutes post-cosyntropin administration, with post-cosyntropin cortisol collection times at hours 30 minutes (±5 minutes), 60 minutes (±5 minutes), and 120 minutes (±5 minutes).

[0196] MAD blood biomarker Endocrine biomarkers will be evaluated throughout the study to assess the role, if any, played by circadian cycles.

[0197] Morning biomarkers: Starting on day -1 and continuing until EOS (or ET), fasting predose blood samples are collected within 15 minutes before dosing for serum cortisol, A4, 17-OHP, aldosterone, ACTH (1 39), renin, and DHEAS. On days when ACTH stimulation tests are performed, these tests are performed approximately 2 hours after study drug administration. Prior to cosyntropin administration, blood samples are collected 2 hours (±15 minutes) after dosing for cortisol, A4, 17-OHP, aldosterone, and DHEA. Cosyntropin is then administered (250 mcg for "high-dose" tests, 1 mcg for "low-dose" tests), defining time 0 for the ACTH stimulation test. 2.5 hours (±15 minutes) after dosing / 30 minutes after cosyntropin administration, blood samples are collected for cortisol measurement. Blood samples are collected 3 hours (±15 minutes) post-dose / 60 minutes post-cosyntropin for measurement of cortisol, A4, 17-OHP, aldosterone, and DHEA.

[0198] Intermediate day biomarkers: Fasting blood samples will be collected for measurement of serum cortisol at 4 hours (±15 minutes) post-dose (approximately 1200 hours) at screening and on days 2, 3, 5, 6, 7, 8, 10, 11, and 12. On days when ACTH stimulation testing is performed, this collection will be 120 minutes post-cosyntropin administration, with post-cosyntropin cortisol collection times at hours 30 minutes (±5 minutes), 60 minutes (±5 minutes), and 120 minutes (±5 minutes).

[0199] 24-hour biomarkers: 24-hour blood biomarker profiles will be measured starting from day -1 to day 1 pre-dose, from day 1 post-dose to day 2 pre-dose, from day 4 post-dose to day 5 pre-dose, and from day 9 post-dose to day 10 pre-dose.

[0200] The first blood sample in the profile is collected as part of the morning (fasting) blood biomarker assessment at 0800 h, and the remaining five samples are collected every 4 h (±15 min) at, for example, 4 h / 1200 h (fasting), 8 h / 1600 h, 12 h / 2000 h, 16 h (fasting), 2400 h (midnight), and 20 h / 0400 h (fasting). At each time point, serum cortisol, A4, 17OHP, and ACTH(1-39) are measured.

[0201] Salivary cortisol For assessment of 24-hour salivary cortisol in the MAD, saliva samples are collected every 4 hours (±15 minutes) starting, for example, pre-dose and at 4 hours / 1200 hours (fasting), 8 hours / 1600 hours, 12 hours / 2000 hours, 16 hours (fasting), 2400 hours (midnight), and 20 hours / 0400 hours (fasting) post-dose.

[0202] Urinary free cortisol (UFC) For assessment of 24-hour UFC in the MAD, urine samples will be collected for 24 hours in three pooled captures at 8-hour (±15-minute) intervals (i.e., 0-8 hours, 8-16 hours, and 16-24 hours). Subjects should void within 30 minutes prior to study drug administration. Urinary creatinine and urine volume output will be measured after each capture.

[0203] Results from the SAD study Pharmacokinetic results from the SAD study are shown in Figure 7. Data shown are mean ± standard error. All doses n=6. Cohort 4 (n=6, 80 mg) was evaluated in a high-dose ACTH stimulation test, while Cohort 5 (n=6, 80 mg) was evaluated in a low-dose ACTH stimulation test. A half-life of ∼24 hours was observed, with a tmax of ∼1 hour at the efficacious dose.

[0204] Compound 1 demonstrated oral bioavailability with dose-proportional exposure.

[0205] Compound 1 was also evaluated in the context of an ACTH stimulation test, in which oral Compound 1 or placebo was administered prior to intravenous (IV) administration of cosyntropin (ACTH(1-24)). In the absence of pharmacological intervention, IV administration of ACTH results in cortisol secretion, whereas pharmacological intervention can suppress unstimulated basal cortisol secretion.

[0206] Oral administration of Compound 1 rapidly reduced basal cortisol output from the adrenal glands. As shown in Figure 8, a rapid reduction in basal cortisol (56% at 80 mg) was observed 2 hours after administration of Compound 1. Complete suppression of cortisol production assumes that no further cortisol is produced upon administration of Compound 1 and that the half-life of cortisol is 66 ± 18 minutes (McKay Li, Cidlowski, JA. Pharmacokinetics of Corticosteroids in Kufe DW et al., editors, Holland-Frei Cancer Medicine 6). th (See ed. Hamilton (ON) 2003). Data shown are mean ± standard error.

[0207] Oral administration of Compound 1 prior to cosyntropin (ACTH(1-24)) demonstrated dose-dependent and potent cortisol suppression (41%) following a suprapathophysiological high-dose ACTH (250 mcg) challenge (Figure 9). The measured % suppression in cortisol AUC was approximately 9%, 22%, 36%, and 41% for the 10 mg, 20 mg, 40 mg, and 80 mg doses, respectively.

[0208] Oral administration of Compound 1 (80 mg) also demonstrated maintenance of normal cortisol levels in a more disease-relevant low-dose ACTH (1 mcg) stimulation challenge, showing a 48% reduction in cortisol levels (Figure 10). In subjects treated with 80 mg of Compound 1, cortisol secretion was suppressed in both high-dose (250 mcg) and low-dose (1 mcg) cosyntropin challenge tests (Figure 11). PBO = placebo. Results from the MAD study

[0209] The pharmacokinetic results on days 1 and 10 from the MAD study using a 40 mg daily dose of Compound 1 over 10 days are shown in Figure 12. Data shown are mean ± standard error. The PK profile and exposure on day 1 were comparable to the single 40 mg dose from the SAD study. The mean half-life was approximately 30 hours. Due to reduced clearance, accumulation with chronic administration was approximately 2.4-fold higher than predicted from the SAD study results.

[0210] In the high-dose ACTH stimulation study, Compound 1 suppressed basal and ACTH-stimulated cortisol levels 10 days after dosing (Figure 13). Compound 1 also suppressed basal and ACTH-stimulated cortisol secretion 4 hours after dosing throughout the MAD study, but no suppression of basal unstimulated cortisol was observed at 24 hours (before the next dose) (Figure 14). Thus, maximal cortisol suppression occurs early in the circadian cycle throughout the MAD study, as observed by 24-hour circadian sampling (Figure 15). PBO = placebo

[0211] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method of treating Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof in a human, comprising administering to the human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 1】

2. 10. The method of claim 1, wherein the human produces excess ACTH.

3. 3. The method of claim 1 or 2, wherein the human has a pituitary adenoma or a corticotroph adenoma.

4. 3. The method of claim 1 or 2, wherein the human has an ectopic ACTH-secreting tumor.

5. 3. The method of claim 1 or 2, wherein the human has a genetic mutation in the adrenal gland that results in impaired cortisol synthesis.

6. 6. The method of claim 5, wherein the human has a mutation in a gene encoding 21β-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase, or a combination thereof.

7. 7. The method of claim 5 or 6, wherein the human has been or is currently receiving exogenous corticosteroids.

8. 8. The method of claim 7, wherein the exogenous corticosteroid is a glucocorticoid.

9. 9. The method of any one of claims 1-8, wherein treating Cushing's disease, CAH, EAS, or a combination thereof comprises reducing levels of ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in the human.

10. 10. The method of any one of claims 1 to 9, wherein treating Cushing's disease or EAS, or a combination thereof, comprises reducing the level of cortisol in the human.

11. 11. The method of any one of claims 1 to 10, wherein treating Cushing's disease or EAS, or a combination thereof, comprises reducing the level of cortisol in blood, serum, saliva, or urine or in the human.

12. 12. The method of any one of claims 1-11, wherein treating Cushing's disease or EAS, or a combination thereof, comprises reducing cortisol levels to an average level in a person without Cushing's disease or EAS, or a combination thereof.

13. 10. The method of any one of claims 1-9, wherein treating CAH comprises reducing levels of steroids, androgens, steroid precursors, or a combination thereof in the human.

14. 14. The method of claim 13, wherein treating CAH comprises reducing the level of A4, 17-OHP, or a combination thereof in the human.

15. 3. The method of claim 1 or 2, wherein the human with Cushing's disease or ectopic ACTH syndrome (EAS) has a non-pituitary tumor that secretes excessive amounts of ACTH, and the non-pituitary tumor is located in the lung, pancreas, thyroid, thymus, intestine, adrenal gland, or paraganglioma.

16. 16. The method of any one of claims 1-15, wherein treating Cushing's disease or EAS comprises reducing fat pad growth (collarbone, back of neck, face and trunk), excessive sweating, dilated capillaries, thinning of skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity, menstrual irregularities, or a combination thereof.

17. 1. A method of treating congenital adrenal hyperplasia (CAH) in a human, comprising administering to the human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 2】

18. 18. The method of claim 17, wherein the human has a genetic mutation that results in impaired cortisol synthesis.

19. 19. The method of claim 17 or 18, wherein the human has a mutation in a gene encoding 21β-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and p450 oxidoreductase, or a combination thereof.

20. The method according to any one of claims 17 to 19, wherein the CAH is classical CAH.

21. 21. The method of claim 20, wherein the classical CAH comprises salt-wasting CAH or simple androgenetic CAH.

22. The method according to any one of claims 17 to 19, wherein the CAH is a non-classical CAH.

23. 23. The method of any one of claims 17-22, wherein treating CAH comprises reducing levels of ACTH-stimulated androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in the human.

24. 23. The method of any one of claims 17-22, wherein treating CAH comprises reducing ACTH-stimulated androgen or cortisol precursor levels in the human.

25. 25. The method of claim 24, wherein the androgen comprises androstenedione (A4).

26. 25. The method of claim 24, wherein the cortisol precursor comprises 17-hydroxyprogesterone (17-OHP).

27. 27. The method of any one of claims 17 to 26, wherein treating CAH comprises reducing androgen secretion.

28. 28. The method of any one of claims 17-27, wherein treating CAH comprises reducing the incidence of inappropriate gonadal development, hyperandrogenism, and mineralocorticoid replacement.

29. 29. The method of any one of claims 17 to 28, wherein said administering Compound 1, or a pharmaceutically acceptable salt or solvate thereof, comprises reducing the exogenous glucocorticoid dosage requirement for said human.

30. 1. A method of reducing fat pad (collarbone, back of neck, face and trunk) growth, excessive sweating, dilated capillaries, thinning of skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity, menstrual irregularities, or a combination thereof, in a human with congenital adrenal hyperplasia (CAH), comprising administering to said human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. 【Transformation 3】

31. 31. The method of claim 30, wherein the administration of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, comprises reducing exogenous glucocorticoid dosage requirements for the human with CAH.

32. 32. The method of claim 31, wherein the exogenous glucocorticoid comprises beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or a combination thereof.

33. 1. A method of reducing ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in a human, comprising administering to the human in need thereof a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 4】

34. 34. The method of claim 33, wherein the human has Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof.

35. 35. The method of claim 33 or 34, wherein reducing the levels of ACTH-stimulated cortisol, A4, 17-OHP, aldosterone, DHEAS, DHEA, or a combination thereof comprises treating Cushing's disease, CAH, EAS, or a combination thereof.

36. 36. The method of any one of claims 1 to 35, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is orally administered once daily or twice daily.

37. 37. The method of any one of claims 1 to 36, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1.

38. 37. The method of any one of claims 1 to 36, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1.

39. Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 37. The method of any one of claims 1 to 36, wherein the compound is administered in an amount equivalent to 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1.

40. A method for treating a disease or condition associated with excess ACTH in a human, comprising administering to the human in need thereof a selective non-peptide small molecule melanocortin 2 receptor (MC2R) antagonist, wherein the non-peptide small molecule MC2R antagonist is about 100-fold selective for MC2R over MC1R, MC3R, MC4R, MC5R, or any combination thereof.

41. 41. The method of claim 40, wherein administering the selective non-peptide small molecule MC2R antagonist to the human having excess ACTH comprises suppressing or reducing pathological elevation of adrenal steroid hormones mediated by ACTH.

42. 42. The method of claim 41, wherein administering the selective non-peptide small molecule MC2R antagonist to the human with excess ACTH comprises suppressing or reducing adrenal-derived cortisol and androgens.

43. 42. The method of claim 41, wherein administration of the selective non-peptide small molecule MC2R antagonist to the human with excess ACTH comprises suppression or reduction of adrenal-derived cortisol and androgens without substantially affecting mineralocorticoid production.

44. 44. The method of any one of claims 40 to 43, wherein the human has elevated cortisol levels.

45. 45. The method of claim 44, wherein the elevated cortisol levels are ACTH-dependent.

46. 46. ​​The method of any one of claims 40 to 45, wherein the human has a pituitary adenoma or a corticotroph adenoma.

47. 47. The method of any one of claims 40 to 46, wherein the human has an ectopic ACTH-secreting tumor.

48. 48. The method of any one of claims 40-47, wherein treating the disease or condition associated with excess ACTH comprises reducing the level of ACTH-stimulated cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof in the human.

49. 48. The method of any one of claims 40-47, wherein treating a disorder associated with excess ACTH comprises reducing the level of cortisol in the human.

50. 50. The method of any one of claims 40 to 49, wherein the disease or condition associated with excess ACTH comprises Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof.

51. A method for treating Cushing's disease, congenital adrenal hyperplasia (CAH), ectopic ACTH syndrome (EAS), or a combination thereof in a human, comprising administering to the human a therapeutically effective amount of a selective non-peptide small molecule MC2R antagonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the cortisol level in the human is reduced by at least 10% from baseline.

52. 52. The method of claim 51, wherein the cortisol level in the human is reduced by at least 10% from baseline and maintained at the reduced level for at least 4 hours.

53. 53. The method of claim 51 or 52, wherein the CAH is classical CAH.

54. 54. The method of claim 53, wherein the classical CAH comprises salt-wasting CAH or simple androgenetic CAH.

55. 53. The method of claim 51 or 52, wherein the CAH is a non-classical CAH.

56. 56. The method of any one of claims 40-55, wherein the selective non-peptide small molecule MC2R antagonist is a compound having the structure of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. 【Transformation 5】

57. 57. The method of claim 56, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is orally administered once daily or twice daily.

58. 58. The method of claim 56 or 57, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1.

59. 58. The method of claim 56 or 57, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1.

60. Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 58. The method of claim 56 or 57, wherein the compound is administered in an amount equivalent to 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1.

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