Therapeutic Uses of Relacorilant, a Heteroaryl-Ketone-Fused Azadecaline Glucocorticoid Receptor Modulator

Abstract

Disclosed are methods and compositions for diagnosing and treating patients suspected of having disorders such as hypercortisolism, metabolic syndrome, prediabetes, diabetes, Cushing's syndrome, Cushing's disease, hyperglycemia secondary to hypercortisolism, liver disease, cardiac disorders, hypertension, blood clotting disorders, cancer, psychological disorders, weight gain, impaired glucose regulation, bone disorders (e.g., osteoporosis), hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH-secreting tumors, peripheral neuropathy, and dyslipidemia. The methods and compositions involve the administration of a heteroaryl-ketone-fused azadecaline glucocorticoid receptor modulator (GRM). A preferred heteroaryl-ketone-fused azadecalin GRM is relacorilant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone). The GRM (e.g., relacorilant) may be administered orally. The GRM (e.g., relacorilant) may be administered orally without food.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to and the benefit of U.S. Provisional Patent Application No. 62 / 809,327, filed February 22, 2019; U.S. Provisional Patent Application No. 62 / 814,441, filed March 6, 2019; and U.S. Provisional Patent Application No. 62 / 833,517, filed April 12, 2019, the entire contents of all of which are incorporated herein by reference. [Background technology]

[0002] Cortisol is a glucocorticoid (GC) hormone that binds to the glucocorticoid receptor. Cortisol acts by binding to the type II glucocorticoid receptor (GR), also known as the cortisol receptor, which is an intracellular receptor that specifically binds cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner and Muller, J. Mol. Endocrinol., 35(2):283-292 (2005)). The term GR encompasses GR isoforms, recombinant GRs, and mutant GRs. Another glucocorticoid receptor is the type I GR, also known as the "mineralocorticoid receptor (MR)," which mediates responses to aldosterone.

[0003] Cortisol is produced in the adrenal glands, but excess cortisol can result from adrenal gland abnormalities (e.g., adrenal tumors). Excess cortisol can be caused by excess adrenocorticotropic hormone (ACTH) released from the pituitary gland, which acts on the adrenal glands to produce excess cortisol. Excess cortisol is sometimes referred to as "hypercortisolemia" or "hypercortisolemia." Patients with hypercortisolemia often also have excess blood sugar (hyperglycemia) and may present with disorders such as low potassium (hypokalemia), high blood pressure, and cardiac problems. Excess cortisol (leading to excessive activation of type II GR) characterizes and causes Cushing's syndrome, a debilitating chronic disease caused by high cortisol levels. Symptoms include hyperglycemia, high blood pressure, heart rhythm disturbances, weight gain (including a characteristic "hump" on the neck or back), hirsutism, and depression.

[0004] When excessive ACTH release from the pituitary gland causes excess cortisol, the disorder is called "Cushing's disease." Such excessive ACTH release from the pituitary gland is usually caused by a pituitary tumor. First-line treatment for Cushing's disease involves surgery to remove the pituitary tumor; however, in many cases, not all of the tumor can be removed (e.g., if the tumor has invaded the cranial region outside the sella turcica, or if it has invaded bone, or for other reasons), or the tumor may regrow, or the tumor may metastasize (more often in the case of non-pituitary (ectopic) tumors than in the case of pituitary tumors). In some cases, radiation therapy is administered after surgery. Conventional chemotherapy treatments, often used for other tumors, may not be applicable to pituitary tumors or may not be suitable for patients with pituitary tumors. Medical therapies to suppress cortisol production or block the effects of cortisol (e.g., mifepristone (formulated as KORLYM®)) are often administered, especially if symptoms persist after surgery. Radiation and standard chemotherapy can have serious side effects and may be unsuitable for Cushing's patients. Therefore, medical (i.e., non-surgical) treatments for pituitary tumors causing Cushing's disease are needed, and improved treatments would be beneficial.

[0005] Patients with other disorders may also exhibit excess cortisol, and excess cortisol may be the cause of such disorders. For example, patients with psychotic major depression typically exhibit excess cortisol. However, there remains a lack of methods and compositions that are effective for reducing the effects of cortisol, particularly those that are effective for reducing the effects of excess cortisol. Summary of the Invention

[0006] Disclosed herein are novel methods for treating a variety of disorders and diseases associated with or caused by excess cortisol (hypercortisolism or hypercortisolism), as well as novel methods for treating a variety of disorders and diseases that can be treated or ameliorated by inhibiting the effects or actions of cortisol. Such diseases and disorders include, but are not limited to, Cushing's syndrome, Cushing's disease, hyperglycemia secondary to hypercortisolism, liver disease (e.g., fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, hepatic fibrosis, and other liver disorders), cardiac disorders (including, e.g., heart rhythm disorders such as QT interval prolongation), hypertension, hypercoagulopathy, cancer, bone disorders, blood clotting disorders, psychological disorders, weight gain (including weight gain caused by psychiatric treatment), metabolic syndrome, pre-diabetes or diabetes, osteoporosis, hypogonadism, pseudoacromegaly, pituitary tumors, functional adrenocorticosteroidism, ACTH-secreting tumors, peripheral neuropathy, and hyperlipidemia. Excess cortisol may be present in patients with metabolic syndrome, prediabetes, or diabetes; or in patients with liver disorders such as fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and liver fibrosis. The methods may include immunotherapeutic treatment. Reducing the effects of hypercortisol can improve the quality of life of patients suffering from hypercortisol or its effects. Reducing the effects of hypercortisol can improve the psychological state of patients suffering from hypercortisol or its effects.

[0007] The methods include administering to the subject an effective amount of a glucocorticoid receptor modulator (GRM) to inhibit the effects of such excess cortisol, and in some embodiments, administering an effective amount of a GRM to the subject in conjunction with another treatment (e.g., another pharmaceutical composition, or a treatment such as surgery, or radiation, or psychotherapy). In some embodiments, the GRM is a non-steroidal GRM. In some embodiments, the GRM is a non-steroidal selective GRM. In some embodiments, the GRM is a non-steroidal heteroaryl-ketone-fused azadecalin-selective GRM compound or a non-steroidal octahydro-fused azadecalin-selective GRM compound. In a preferred embodiment, the GRM is a non-steroidal heteroaryl-ketone fused azadecalin selective GRM compound having the chemical name (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, termed "relacorilant," having the formula: [ka]

[0008] In some embodiments, the methods disclosed herein involve administering a GRM, such as the heteroaryl-ketone-fused azadecalin GRM relacorilant, to a patient in need of such treatment to treat a disorder selected from diseases and disorders such as Cushing's syndrome; Cushing's disease; hyperglycemia secondary to hypercortisolism; metabolic syndrome, prediabetes, or diabetes; liver disease (e.g., liver disorders such as fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and hepatic fibrosis); cardiac disorders (e.g., including heart rhythm disorders such as QT interval prolongation, with or without left ventricular hypertrophy (LVH)); hypertension; cancer; psychological disorders (e.g., depression, such as psychotic major depression); and weight gain (including weight gain caused by psychiatric treatment). A GRM, such as relacorilant, can be administered to a patient as monotherapy; in some embodiments, a GRM, such as relacorilant, can be administered to a patient in conjunction with another treatment. The GRM can be administered before, after, or together with another treatment, or in any combination thereof. Additionally, the methods disclosed herein include administering a GRM, such as relacorilant, to a patient in need of diagnosis, e.g., to diagnose a disorder, such as Cushing's disease.

[0009] In some cases, the GRM (e.g., relacorilant) is administered orally. In some embodiments, the GRM is administered with food. In some embodiments, the GRM is administered to a fasting patient. In some cases, the GRM (e.g., relacorilant) is administered with at least one other medication. In some cases, the GRM (e.g., relacorilant) is administered after the subject or patient has been administered at least one other medication. In some cases, the GRM (e.g., relacorilant) is administered before the subject or patient has been administered at least one other medication. In some cases, the GRM (e.g., relacorilant) is administered to the subject after the subject or patient has undergone surgery. In some cases, the GRM (e.g., relacorilant) is administered to the subject before the subject or patient has undergone surgery. [Brief explanation of the drawings]

[0010] [Figure 1] Patients who achieved clinically meaningful suppression of HbA1c, 2-hour oGTT, or antidiabetic medication use. [Figure 2] Patients who achieved clinically meaningful improvement in hypertension (high blood pressure). [Figure 3] Effect of relacorilant on coagulation. Patients with Cushing's syndrome are at high risk for thrombotic events; however, patients with Cushing's syndrome treated with relacorilant showed improvements in clotting factors. These results suggest that relacorilant may be useful in improving preoperative coagulation control (before surgery for Cushing's syndrome) in patients with Cushing's syndrome who are at high risk for thrombotic events. DETAILED DESCRIPTION OF THE INVENTION

[0011] (Introduction) The methods disclosed herein can be used to treat a patient having a disorder by administering an effective amount of a glucocorticoid receptor modulator (GRM), such as a selective glucocorticoid receptor modulator (SGRM), which in a preferred embodiment is relacorilant (sometimes referred to as "RELA"). In various embodiments, the methods disclosed herein involve administering a GRM, such as relacorilant, to a patient in need of such treatment to treat a disorder selected from Cushing's syndrome; Cushing's disease; hyperglycemia secondary to hypercortisolism; metabolic syndrome, prediabetes, or diabetes; liver disease (e.g., liver disorders such as fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and hepatic fibrosis); cardiac disorders (e.g., left ventricular hyperplasia, pulmonary edema, and pulmonary fibrosis); Diseases and disorders include: heart rhythm disorders such as QT interval prolongation, with or without LVH; hypertension; hypercoagulopathy; cancer; psychological disorders (e.g., depression, such as psychotic major depression); weight gain (including weight gain caused by psychiatric treatment); bone disorders; blood disorders, such as blood clotting disorders; osteoporosis, hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH-secreting tumors, peripheral neuropathy, and dyslipidemia. A GRM or SGRM, such as relacorilant, may be administered with an immunotherapeutic agent, such as a checkpoint inhibitor, or other pharmaceutical agent. The methods disclosed herein can be used to treat patients with any of the disorders indicated by the results disclosed in Table 1. The methods disclosed herein can be used to normalize any of the diagnostic results indicated by the results disclosed in Table 1 in patients.

[0012] The methods disclosed herein, comprising administering a GRM such as relacorilant, can be used to diagnose a patient suspected of having a disorder selected from the following: Cushing's syndrome; Cushing's disease; hyperglycemia secondary to hypercortisolism; metabolic syndrome, prediabetes, or diabetes; liver disease (e.g., liver disorders such as fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and hepatic fibrosis); cardiac disorders (including, e.g., heart rhythm disorders such as QT interval prolongation, with or without left ventricular hypertrophy (LVH)); hypertension; hypercoagulopathy; cancer; psychological disorders (e.g., depression such as psychotic major depression); weight gain (including weight gain caused by psychiatric treatment); bone disorders; and blood clotting disorders. The methods disclosed herein, comprising administering a GRM such as relacorilant, can be used to improve the quality of life of patients. The methods disclosed herein, including administering a GRM such as relacorilant, can be used to diagnose patients suspected of having any of the disorders shown by the results disclosed in Table 1.

[0013] A GRM or SGRM, such as relacorilant, can be administered to a patient as monotherapy; in some embodiments, a GRM, such as relacorilant, can be administered to a patient along with another treatment. The GRM can be administered before, after, or together with the other treatment, or in any combination thereof. Additionally, methods disclosed herein include administering a GRM, such as relacorilant, to a patient in need of diagnosis, e.g., to diagnose a disorder, such as Cushing's disease.

[0014] In some embodiments, the GRM is a non-steroidal GRM.

[0015] In some cases, the GRM (e.g., SGRM) is a non-steroidal compound that includes a heteroaryl ketone-fused azadecalin structure. In some cases, the heteroaryl ketone-fused azadecalin compound has the formula: [ka] In the formula, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally R 1a and each R is substituted with 1 to 4 groups independently selected from 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, N-oxide, C 3-8 Cycloalkyl, and C 3-8 ring J is selected from the group consisting of cycloalkyl rings, heterocycloalkyl rings, aryl rings, and heteroaryl rings, wherein the heterocycloalkyl rings and heteroaryl rings have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; and each R 2 is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R 2c optionally substituted with a group; or two R 2groups together form an oxo group (=O); or two R 2 The groups taken together form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, and 1 to 3 R 2d forming a heterocycloalkyl ring optionally substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 alkyl; each R 2c are independently hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, and -NR 2a R 2b each R 2d are independently hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups together form (=O); R 3 are 1 to 4 R 3a and each R is selected from the group consisting of phenyl and pyridyl, optionally substituted with a group; 3a are independently hydrogen, halogen, and C 1-6 haloalkyl; the subscript n is an integer from 0 to 3; or the heteroaryl ketone-fused azadecalin compound is a salt or isomer thereof. Such compounds include relacolinants, and are disclosed in U.S. Pat. No. 8,559,784, the entire contents of which are incorporated herein by reference. Uses and discussions of such compounds are further disclosed in U.S. Pat. Nos. 9,273,047; 9,943,505; 9,707,223; 9,956,216; 10,117,852; and 10,151,763, the entire contents of which are incorporated herein by reference.

[0016] In a preferred embodiment, the GRM is a non-steroidal heteroaryl-ketone fused azadecalin GRM compound having the chemical name (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, termed "relacorilant," having the formula: [ka] In some embodiments, the GRM is a non-steroidal heteroaryl-ketone fused azadecalin GRM compound designated "CORT122928," which has the following formula: (R)-(1-(4-fluoro(fluro)phenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone. [ka] In some embodiments, the GRM is a non-steroidal heteroaryl-ketone fused azadecalin GRM compound having the chemical name (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, designated "CORT113176," having the following formula: [ka]

[0017] In some cases, the GRM (e.g., SGRM) is a non-steroidal compound comprising an octahydro-fused azadecalin structure. Exemplary GRMs comprising an octahydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082, which can be prepared as described in that patent, the disclosure of which is incorporated herein by reference in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the octahydro-fused azadecalin compound has the formula: [ka] During the ceremony, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 1a optionally substituted with 1 to 4 groups independently selected from Each R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl and C having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 The groups taken together form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, and 1 to 3 R 2c forming a heterocycloalkyl ring optionally substituted with a group; R 2a , R 2b , and R 2c are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; Each R 3a are independently halogen; The subscript n is an integer between 0 and 3; or salts and isomers thereof.

[0018] In some embodiments, the octahydro-fused azadecalin compound has the formula: [ka] In the formula, R 1 are optionally each independently R 1a and each R is selected from the group consisting of pyridine and thiazole, each substituted with 1 to 4 groups selected from 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 haloalkyl, and -CN; R 3a is F; the subscript n is an integer from 0 to 3; or R 1 is selected from salts and isomers thereof.

[0019] In some embodiments, the GRM is a non-steroidal octahydro-fused azadecalin GRM compound having the chemical name ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, designated "CORT125281," having the formula: [ka] In some embodiments, the GRM has the following formula and is a non-steroidal octahydro-fused azadecalin GRM compound designated "CORT125329" and having the chemical name ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone. [ka]

[0020] (definition) As used herein, the term "subject" or "patient" refers to a human or non-human organism. That is, the methods and compositions described herein are applicable to both human and animal diseases. In some embodiments, a subject is a "patient," i.e., a living human undergoing medical treatment for a disease or condition. This includes individuals without established disease who are being investigated for signs of pathology. Preferred subjects are those who have already been diagnosed with Cushing's syndrome, an example of a disease that can be treated by the compositions and methods of the present invention.

[0021] A disease, disorder, abnormality, adverse event, or condition that causes discomfort, distress, or ill-health may be referred to as a "pathological condition." For example, a pathological condition associated with a disease or disorder, such as hypercortisolism, Cushing's syndrome, or Cushing's disease, may be referred to as a "complication."

[0022] Acronyms used herein include the following: ACTH adrenocorticotropic hormone proACTH (proprotein of ACTH) POMC Proopiomelanocortin aPTT Activated partial thromboplastin time ALT alanine aminotransferase (or "serum glutamate-pyruvate aminotransferase" (SGPT)) AST aspartate aminotransferase (or "serum glutamate-oxaloacetate aminotransferase" (SGOT)) AUC area under the concentration-time curve AUC 0-24h Area under the concentration-time curve over 24 hours AUC グルコース Area under the concentration-time curve for glucose AUC インスリン Area under the concentration-time curve for glucose The Beck Depression Inventory (BDI) is a 21-question self-report questionnaire assessing depression. BDI-II Total Score is the total score of the Beck Depression Inventory II. Cushing's Syndrome QOL Score Cushing's Syndrome Quality of Life Score. A patient questionnaire assessing health-related quality of life in patients with Cushing's syndrome ECG electrocardiogram HOMA-IR Homeostasis Model Assessment (HOMA) Insulin Resistance (IR) IR insulin resistance HbA1c glycated hemoglobin IGT Impaired glucose tolerance (sometimes diagnosed as oGTT) mITT (modified intention to treat) mPP modified protocol population NTx N-telopeptides of type 1 collagen oGTT oral glucose tolerance test PR interval: The time from the start of the P wave to the start of the R (peak of the QRS complex) QRS time: The time from the start of the Q wave to the return of the S wave to baseline QT interval: The time from the start of the QRS complex to the return of the T wave to baseline QTcB interval Corrected QT interval (Bazett's correction) RR interval: The time between two R waves (peaks of the QRS complex) UFC Urinary free cortisol Urinary NTx Urinary N-telopeptides cross-links

[0023] As used herein, the term "adrenocorticotropic hormone" (ACTH) refers to a peptide hormone produced by the anterior pituitary gland that stimulates the adrenal cortex to secrete glucocorticoid hormones that support cellular glucose synthesis, catabolize proteins, mobilize free fatty acids, and inhibit inflammation in allergic responses. One such glucocorticoid hormone is cortisol, which regulates carbohydrate, fat, and protein metabolism.

[0024] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a drug effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" can refer to an amount of a functional agent or pharmaceutical composition effective to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. An effective amount can be an amount effective to reduce symptoms such as hypercortisolism, hyperglycemia, hypertension, liver fat, liver fibrosis, or depression, or to achieve other desired beneficial clinical results related to patient improvement.

[0025] As used herein, the terms "administer," "administering," "administered," or "administration" refer to giving a compound or composition (e.g., a compound or composition described herein) to a subject or patient.

[0026] As used herein, the term "fasting" refers to a subject or patient not eating for at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or more. In a preferred embodiment, a subject or patient in a fasting state has not eaten for at least 4 hours. When a pharmaceutical composition is administered to a subject or patient in a fasting state, the pharmaceutical composition is administered without food, and the subject or patient should not eat for at least 1 hour after administration of the drug.

[0027] As used herein, the terms "hypercortisolism" and "hypercortisolism" are synonymous and refer to an excess of cortisol. Patients with hypercortisolism have Cushing's syndrome and may have symptoms and other disorders caused by or associated with such cortisol excess.

[0028] As used herein, the term "Cushing's syndrome" refers to a disorder caused by excessive activity of the stress hormone cortisol. Endogenous Cushing's syndrome is a rare disease that most commonly affects adults between the ages of 20 and 50. In many cases, the disease is caused by a pituitary tumor or an adrenal tumor. Symptoms vary, but most patients experience one or more of the following: hyperglycemia, metabolic syndrome, prediabetes, or diabetes, high blood pressure, upper body obesity, a round face, increased fat around the neck, thinning of the arms and legs, severe fatigue, and muscle weakness. Irritability, anxiety, cognitive impairment, and depression are also common. Cushing's syndrome can affect any organ system in the body and can be fatal if not treated effectively.

[0029] As used herein, the term "metabolic syndrome" refers to a syndrome characterized by components such as hyperglycemia, high blood pressure, excess body fat (especially around the waist), and high levels of blood lipids. Metabolic syndrome may indicate an increased risk of diseases such as cardiovascular disease, diabetes, and liver disease.

[0030] As used herein, the term "prediabetes" refers to a condition in which a subject may have one or more of the following: elevated blood glucose, abnormal glucose tolerance test results, and other symptoms, such as elevated blood pressure, excess weight, excess blood lipids, etc., although such excesses or abnormalities may be mild.

[0031] As used herein, the term "diabetes" refers to a disorder of blood glucose characterized by high blood glucose levels, impaired insulin response, the presence or high levels of ketones in the urine, and other symptoms known in the clinical art. Patients often present with symptoms such as dry mouth, frequent urination, fatigue, and irritability.

[0032] As used herein, the term "immunotherapy" refers to a disease treatment, typically cancer treatment, that affects a patient's immune system (e.g., by activating or suppressing its action). Some immunotherapies involve the administration of "checkpoint inhibitors," which enhance the action of immune system T cells to attack cancer cells. Some immunotherapies involve the use of patient T cells exposed to cancer cells or cancer markers to enhance the treatment of cancer in the patient.

[0033] As used herein, the term "checkpoint inhibitor" refers to a drug, which may be, for example, a small molecule drug or an antibody, that inhibits the action of a protein or other aspect of an immune system cell that reduces or blocks the ability of T cells to attack cancer cells. The target of a checkpoint inhibitor may be in or on a T cell, or may be in or on a cancer cell. Targets of checkpoint inhibitors include proteins such as PD-1, PDL-1, CTLA-4, B7-1, and B7-2. Checkpoint inhibitors include antibodies against PD-1, PDL-1, CTLA-4, B7-1, and B7-2. For example, the antibody drugs pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo) inhibit PD-1, while the antibody drugs atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) inhibit PDL-1.

[0034] As used herein, the term "combination therapy" refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously or sequentially in any order during all or part of the treatment period. The at least two agents may be administered according to the same dosing schedule or according to different dosing schedules. Optionally, one agent is administered according to a scheduled schedule and the other agent is administered intermittently. Optionally, both agents are administered intermittently. In some embodiments, one pharmaceutical agent, e.g., an SGRM, is administered daily and the other pharmaceutical agent, e.g., a pharmaceutical agent, is administered every two, three, or four days.

[0035] As used herein, the term "compound" is used to refer to a molecular component of a unique, identifiable chemical structure. A molecular component ("compound") may exist in the form of a free species, unassociated with other molecules. A compound may also exist as part of a larger aggregate, associated with other molecules but retaining its chemical identity. A solvate, in which a molecular component ("compound") of defined chemical structure is associated with molecules of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. A "compound" refers to the molecular component (the structure of which is shown) itself, whether it exists in free or associated form.

[0036] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as far as any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated. Supplementary active compounds can also be incorporated into the composition.

[0037] The terms "glucocorticoid" ("GC") or "glucocorticosteroid" refer collectively to steroid hormones that bind to the glucocorticoid receptor. GCs typically have 21 carbon atoms and are characterized by an α,β-unsaturated ketone in ring A with an α-ketol group attached to ring D. GCs vary in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19. See Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," Biochemistry, Daisy et al. (eds.), 1989, p. 567.

[0038] The mineralocorticoid receptor (MR), also known as the type I glucocorticoid receptor (GRI), is activated by aldosterone in humans.

[0039] As used herein, the term "glucocorticoid receptor" ("GR") refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs. Glucocorticoid receptors are also referred to as cortisol receptors. This term encompasses GR isoforms, recombinant GRs, and mutant GRs. "Glucocorticoid receptor" ("GR") refers to type II GRs that specifically bind cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner and Muller, J. Mol. Endocrinol., October 1, 2005, Vol. 35, pp. 283-292).

[0040] "Glucocorticoid receptor modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of GR to an agonist. For example, GR agonists such as dexamethasone increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). Thus, GR modulators of the present invention can be identified by measuring the ability of the compound to modulate the effects of dexamethasone. TAT activity can be measured as summarized in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Modulators can be identified by measuring the ability of the compound to modulate the effects of dexamethasone. TAT activity can be measured as summarized in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. 50 (50% effective concentration) of less than 10 micromolar. See Example 1 below.

[0041] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates any biological response associated with the binding of GR to an agonist. By "selective," the agent preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). A selective glucocorticoid receptor modulator is one that binds preferentially to GR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR with an affinity (K) that is 10-fold greater than its affinity. d In a more preferred embodiment, the selective glucocorticoid receptor modulator binds to the GR with an affinity (K) that is 100-fold greater than its affinity for the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR. d In another embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000-fold greater (1 / 1000 of the Kd value) than its affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR.

[0042] As used herein, the terms "selective glucocorticoid receptor modulator" and "SGRM" do not include ORG34517, or 11-(substituted phenyl)-estra-4,9-diene derivatives, or 11-(substituted phenyl)-estra-4,9-diene derivatives of the formula: [ka] wherein A is a residue of a 5- or 6-membered ring which is not bonded to one another and contains two heteroatoms independently selected from O and S, and which are optionally substituted with one or more halogen atoms; or A is a residue of a 5- or 6-membered ring which does not have a double C-C bond and contains one heteroatom selected from O and S, which heteroatom is attached to a phenyl group at the position indicated by an asterisk, and which is optionally substituted with one or more halogen atoms; R l is H or I-oxo(1-4C)alkyl; R2 is H, (1-8C)alkyl, halogen, or CF3; X is selected from (H, OH), O, and NOH; and the dashed line represents an optional bond (see, for example, claim 1 of U.S. Pat. No. 8,658,128).

[0043] As used herein, the term "composition" is intended to encompass products containing specified amounts of specified components, such as the compounds, their tautomeric forms, derivatives, analogs, stereoisomers, polymorphs, deuterated species, pharmaceutically acceptable salts, esters, ethers, metabolites, isomeric mixtures, pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions, as well as any product that results directly or indirectly from combining specified amounts of specified components. With respect to pharmaceutical compositions, this term is intended to encompass products containing an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

[0044] In some embodiments, the term "consisting essentially of" refers to the composition being formulated with the labeled active ingredient as the only active ingredient, although other compounds may be included for formulation stabilization, preservation, etc., but which are not directly involved in the therapeutic effect of the labeled active ingredient. In some embodiments, the term "consisting essentially of" may refer to a composition containing the active ingredient and ingredients that facilitate the release of the active ingredient. For example, a composition may contain one or more ingredients that provide sustained release of the active ingredient to a subject over time. In some embodiments, the term "consisting of" refers to a composition containing the active ingredient and a pharmaceutically acceptable carrier or excipient.

[0045] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of (and absorption by) an active agent to a subject and can be included in the compositions of the invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those of skill in the art will recognize that other excipients are useful in the present invention.

[0046] As used herein, the term "nonsteroidal backbone" in reference to an SGRM means that the SGRM does not share structural homology with, or is not a modification of, cortisol, which has a steroid backbone containing 17 carbon atoms bonded together in four fused rings. Such compounds include synthetic protein mimetics and analogs, including partially peptidic, pseudopeptidic, and nonpeptidic molecular entities.

[0047] Non-steroidal SGRM compounds include SGRMs containing a fused azadecalin structure (sometimes referred to as a fused azadecalin backbone), SGRMs containing a heteroaryl ketone-fused azadecalin structure (sometimes referred to as a heteroaryl ketone-fused azadecalin backbone), and SGRMs containing an octahydro-fused azadecalin structure (sometimes referred to as an octahydro-fused azadecalin backbone). Examples of non-steroidal glucocorticoid receptor modulators containing a fused azadecalin structure include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Examples of non-steroidal glucocorticoid receptor modulators containing a heteroaryl ketone-fused azadecalin structure include those described in U.S. Patent No. 8,859,774 and its continuations. Examples of non-steroidal glucocorticoid receptor modulators containing an octahydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082. The entire contents of all patents and patent applications referenced herein are hereby incorporated by reference in their entirety.

[0048] Where substituents are specified in a conventional chemical formula written from left to right, chemically identical substituents are equivalently included as would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0049] "Alkyl" refers to a straight or branched chain, saturated, aliphatic radical having the number of carbon atoms specified. Alkyl can contain any number of carbons, for example, C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C5-6 For example, C 1-6 Alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec - Butyl, tert - Examples include, but are not limited to, butyl, pentyl, isopentyl, and hexyl.

[0050] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. For alkyl groups, an alkoxy group is C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0051] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0052] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced by halogen atoms. For alkyl groups, haloalkyl groups are C 1-6 and the like, including trifluoromethyl, fluoromethyl, and the like.

[0053] The term "perfluoro" can be used to define a compound or radical in which all hydrogens have been replaced with fluorines. For example, perfluoromethane includes 1,1,1-trifluoromethyl.

[0054] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms have been replaced with halogen atoms. For alkyl groups, the haloalkoxy group is C 1-6The alkoxy group may have any suitable number of carbon atoms, such as . The alkoxy group may be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, for example, fluorine, the compound is a fully substituted, for example, fully fluorinated, compound. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0055] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms or the number of atoms specified. A cycloalkyl can contain any number of carbons, e.g., C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 and the like. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic cycloalkyl rings and saturated polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3-isomer and 1,4-isomer), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-isomer, 1,4-isomer, and 1,5-isomer), norbornene, and norbornadiene. When the cycloalkyl is a saturated monocyclic C 3-8When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Additional heteroatoms may be useful, including, but not limited to, B, Al, Si, and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring atoms, such as, for example, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in a heterocycloalkyl group, such as, for example, 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be fused with aromatic or non-aromatic ring systems to form building blocks, including, but not limited to, indoline.

[0057] When a heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative elements include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, representative elements include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0058] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and can contain 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0059] "Heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms may be used, including, but not limited to, B, Al, Si, and P. The heteroatoms may also be oxidized, such as, but not limited to, N-oxide, -S(O)-, and -S(O)2-. Heteroaryl groups can contain any number of ring atoms, such as, for example, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl group, for example, 1, 2, 3, 4, or 5; or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems, such as phenyl rings, to form entities including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings joined by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0060] The heteroaryl group may be attached at any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-, 3-, and 4-pyridine; imidazole includes 1-, 2-, 4-, and 5-imidazole; pyrazole includes 1-, 3-, 4-, and 5-pyrazole; triazole includes 1-, 4-, and 5-triazole; tetrazole includes 1- and 5-tetrazole; pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine; pyridazine includes 3- and 4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazine includes 3-, 5-, and 6-triazine; 1,3,5-triazine includes 2-triazine; thiophene includes 2- and 3-thiophene; and furan includes 2- and 3-furan. thiazoles include 2-, 4-, and 5-thiazoles; isothiazoles include 3-, 4-, and 5-isothiazoles; oxazoles include 2-, 4-, and 5-oxazoles; isoxazoles include 3-, 4-, and 5-isoxazoles; indole includes 1-, 2-, and 3-indole; isoindole includes 1- and 2-isoindole; quinoline includes 2-, 3-, and 4-quinoline; isoquinoline includes 1-, 3-, and 4-isoquinoline; quinazoline includes 2- and 4-quinoazoline; cinnoline includes 3- and 4-cinnoline; benzothiophene includes 2- and 3-benzothiophene; and benzofuran includes 2- and 3-benzofuran.

[0061] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring heteroatoms including N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0062] Some heteroaryl groups have 5 to 10 ring members and only nitrogen as a heteroatom, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups have 5 to 10 ring members and only oxygen as a heteroatom, such as furan and benzofuran. Some other heteroaryl groups have 5 to 10 ring members and only sulfur as a heteroatom, such as thiophene and benzothiophene. Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.

[0063] "Heteroatom" refers to O, S, or N.

[0064] "Salt" refers to an acid salt or a base salt of the compound used in the method of the present invention. Examples of pharmaceutically acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). These pharmaceutically acceptable salts are understood to be non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0065] "Isomers" refer to compounds that have the same chemical formula but are structurally distinguishable.

[0066] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0067] The description of the compounds of the present invention is constrained by the principles of chemical bonding known to those skilled in the art, i.e., where groups may be substituted with one or more substituents, such substitutions are selected to be consistent with the principles of chemical bonding and to produce compounds that are not substantially unstable and / or that those skilled in the art know may be unstable under ambient conditions, such as aqueous, neutral, or physiological conditions.

[0068] The methods disclosed herein can be applied to treat patients with disorders such as Cushing's syndrome, Cushing's disease, caused by, characterized by, or symptomatically including: excess cortisol (hypercortisolism); hyperglycemia secondary to hypercortisolism; metabolic syndrome, prediabetes, or diabetes; liver disease (e.g., liver disorders such as fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and hepatic fibrosis); cardiac disorders (including, e.g., heart rhythm disorders such as QT interval prolongation with or without left ventricular hypertrophy (LVH)); hypertension; cancer; psychological disorders (e.g., depression such as psychotic major depression); and weight gain (including weight gain caused by psychiatric treatment).

[0069] In general, treatment of excess cortisol (hypercortisolemia) can be achieved by administering an effective amount of a pharmaceutical agent in combination with an effective amount of a glucocorticoid receptor modulator (GRM) of any chemical structure or mechanism of action. In some embodiments, the GRM is a selective GRM (SGRM). In some embodiments, treatment of excess cortisol can be achieved by administering an effective amount of a pharmaceutical agent in combination with an effective amount of an SGRM. In preferred embodiments, treatment of excess cortisol can be achieved by administering an effective amount of a pharmaceutical agent in combination with an effective amount of a non-steroidal SGRM. Exemplary GRM classes, particularly exemplary non-steroidal SGRM classes, and specific members of such classes are provided herein. However, one of skill in the art will readily recognize other related or unrelated GRMs and SGRMs that can be used in the treatment methods described herein.

[0070] Exemplary GRMs comprising heteroaryl ketone-fused azadecalin structures include those described in U.S. Patent No. 8,859,774, which can be prepared as disclosed therein and is incorporated herein by reference in its entirety. Such exemplary GRMs may be SGRMs. In some cases, the GRM comprising heteroaryl ketone-fused azadecalin structures has the following structure: [ka] During the ceremony, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally R 1a each independently substituted with 1 to 4 groups selected from Each R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, N-oxide, C 3-8Cycloalkyl, and C 3-8 heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of 1 to 4 R 2c optionally substituted with a group; Alternatively, two R attached to the same carbon 2 The groups together form an oxo group (=O); Or, two R 2 groups taken together form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally 1 to 3 R 2d substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; Each R 2c are independently hydrogen, halogen, hydroxy, C1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, and -NR 2a R 2b selected from the group consisting of: Each R 2d are independently hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups together form (=O); R 3 are 1 to 4 R 3a selected from the group consisting of phenyl and pyridyl, optionally substituted with a group; Each R 3a are independently hydrogen, halogen, and C 1-6 haloalkyl; The subscript n is an integer between 0 and 3; or salts and isomers thereof.

[0071] In a preferred embodiment, the GRM is a non-steroidal heteroaryl-ketone fused azadecalin GRM compound having the chemical name (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, termed "relacorilant," having the formula: [ka]

[0072] Exemplary GRMs containing octahydro-fused azadecalin structures include those described in U.S. Pat. No. 10,047,082, which can be prepared as described therein, the disclosure of which is incorporated herein by reference in its entirety. Such exemplary GRMs can be SGRMs. In some cases, the GRM containing octahydro-fused azadecalin structures has the following structure: [ka] During the ceremony, R 1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each independently selected from the group consisting of R 1a substituted with 1 to 4 groups selected from; Each R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2groups taken together form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally 1 to 3 R 2c heterocycloalkyl rings substituted with groups; R 2a , R 2b , and R 2c are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; Each R 3a are independently halogen; The subscript n is an integer between 0 and 3; or salts and isomers thereof.

[0073] In some embodiments, the octahydro-fused azadecalin compound has the formula: [ka] In the formula, R 1 are optionally each independently R 1a and each R is selected from the group consisting of pyridine and thiazole, each substituted with 1 to 4 groups selected from 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 haloalkyl, and -CN; R 3a is F; the subscript n is an integer from 0 to 3; or R 1 is selected from salts and isomers thereof.

[0074] Exemplary glucocorticoid receptor antagonists containing an octohydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082. In some embodiments, the octahydro-fused azadecalin compound is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone ("CORT125281"), which has the following structure: [ka]

[0075] In some embodiments, the GRM has the following formula and is a non-steroidal octahydro-fused azadecalin GRM compound designated "CORT125329" and having the chemical name ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone. [ka]

[0076] To determine whether a test compound is an SGRM, the compound is first subjected to an assay to measure its ability to bind to GR and inhibit GR-mediated activity, thereby determining whether the compound is a glucocorticoid receptor modulator. If the compound is confirmed to be a glucocorticoid receptor modulator, the compound is then subjected to a selectivity test to determine whether the compound can specifically bind to GR compared to proteins other than GR, such as the estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor. In one embodiment, the SGRM binds to GR with substantially higher affinity, e.g., at least 10-fold higher affinity, than to proteins other than GR. The SGRM may exhibit 100-fold, 1000-fold, or more selectivity for binding to GR relative to proteins other than GR.

[0077] The ability of a test compound to bind to the glucocorticoid receptor can be measured using various assays, for example, by screening the test compound for its ability to compete with a glucocorticoid receptor ligand, such as dexamethasone, for binding to the glucocorticoid receptor. Those skilled in the art will recognize that there are several methods for performing such competitive binding assays. In some embodiments, the glucocorticoid receptor is pre-incubated with a labeled glucocorticoid receptor ligand before contacting it with the test compound. This type of competitive binding assay is sometimes referred to as a binding displacement assay. A decrease in the amount of labeled ligand bound to the glucocorticoid receptor indicates that the test compound is binding to the glucocorticoid receptor. In some cases, the labeled ligand is a fluorescently labeled compound (e.g., a fluorescently labeled steroid or steroid analog). Alternatively, the binding ability of the test compound to the glucocorticoid receptor can be directly measured using a labeled test compound. This latter type of assay is referred to as a direct binding assay.

[0078] Both direct binding assays and competitive binding assays can be used in a variety of formats. These formats may be similar to those used in immunoassays and receptor binding assays. For descriptions of various formats of binding assays, including competitive binding assays and direct binding assays, see Basic and Clinical Immunology, 7th Edition (D. Stites and A. Terr (eds.)) 1991; Enzyme Immunoassay, E.T. Maggio (ed.), CRC Press, Boca Raton, FL (1980); and "Practice and Theory of Enzyme Immunoassays," P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers BV, Amsterdam (1985), each of which is incorporated herein by reference.

[0079] For example, in a solid-phase competitive binding assay, a sample compound can compete with a labeled analyte for specific binding sites on a binding agent bound to a solid surface.In this type of format, the labeled analyte can be a glucocorticoid receptor ligand, and the binding agent can be a glucocorticoid receptor bound to a solid phase.Alternatively, the labeled analyte can be a labeled glucocorticoid receptor, and the binding agent can be a solid-phase glucocorticoid receptor ligand.The concentration of the labeled analyte bound to the capture agent is inversely proportional to the competitive ability of the test compound in the binding assay.

[0080] Alternatively, competitive binding assays may be performed in liquid phase, and any of a variety of techniques known in the art may be used to separate bound from unbound labeled protein. For example, several methods have been developed to distinguish between bound and excess ligand, or between bound and unbound test compound. These include identification of bound complexes by sucrose gradient centrifugation, gel electrophoresis, or gel isoelectric focusing; precipitation of receptor-ligand complexes with protamine sulfate or adsorption on hydroxylapatite; and removal of unbound compound or ligand by adsorption on dextran-coated charcoal (DCC) or binding to immobilized antibodies. After separation, the amount of bound ligand or test compound is determined.

[0081] Alternatively, a homogenous binding assay may be performed that does not require a separation step. For example, the label on the glucocorticoid receptor may be altered by binding of the glucocorticoid receptor to its ligand or test compound. This change in the labeled glucocorticoid receptor results in a decrease or increase in the signal emitted by the label, and measurement of the label at the end of the binding assay allows for detection or quantification of the bound glucocorticoid receptor. A wide variety of labels can be used. Components can be labeled by any one of several methods. Useful radioactive labels include: 3 H, 125 I, 35 S, 14 C, or 32Useful non-radioactive labels include those incorporating P. Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent materials, phosphorescent materials, electrochemiluminescent materials, etc. Fluorescent materials are particularly useful in analytical methods used to detect shifts in protein structure, such as fluorescence anisotropy and / or fluorescence polarization. The choice of label is based on the required sensitivity, ease of conjugation with the compound, stability requirements, and available instrumentation. For a review of various labeling or signal-producing systems that can be used, see U.S. Pat. No. 4,391,904, incorporated herein by reference in its entirety for all purposes. The label can be directly or indirectly attached to the desired component of the assay according to methods well known in the art. In some cases, a test compound is contacted with GR in the presence of a fluorescently labeled ligand (e.g., a steroid or steroid analog) with known affinity for GR, and the amount of bound and free labeled ligand is estimated by measuring the fluorescence polarization of the labeled ligand.

[0082] ii.Activity 1) HepG2 tyrosine aminotransferase (TAT) assay Compounds that exhibit the desired binding affinity to GR are tested for their activity in inhibiting GR-mediated activity. These compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay), which measures the ability of a test compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone. See Example 1. GR modulators suitable for the methods disclosed herein have an IC of less than 10 micromolar. 50 (50% inhibitory concentration). Other assays, including but not limited to those described below, can also be used to confirm the GR modulating activity of a compound.

[0083] 2) Cell-based assays Cell-based assays requiring whole cells or cell fractions containing glucocorticoid receptors can also be used to measure the binding ability of test compounds or their ability to modulate glucocorticoid receptor activity. Exemplary cell types that can be used in the methods of the present invention include any mammalian cell, including, for example, leukocytes (such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes such as T cells and B cells), leukemia cells, Burkitt's lymphoma cells, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, myocytes, breast tumor cells, ovarian cancer carcinomas, cervical cancer, glioblastoma, hepatocytes, kidney cells, and neuronal cells, as well as fungal cells, including yeast. Cells can be primary cells, tumor cells, or other types of immortal cell lines. Of course, glucocorticoid receptors can be expressed in cells that do not express endogenous forms of glucocorticoid receptors.

[0084] In some cases, glucocorticoid receptor fragments and even protein fusions can be used for screening. When a molecule that competes with a glucocorticoid receptor ligand in binding is desired, the GR fragment used is a fragment that can bind to the ligand (e.g., dexamethasone). Alternatively, any fragment of GR can be used as a target to identify molecules that bind to the glucocorticoid receptor. Glucocorticoid receptor fragments can include, for example, any fragment consisting of at least 20, at least 30, at least 40, or at least 50 amino acids, up to a protein containing all but one amino acid of the glucocorticoid receptor.

[0085] In some embodiments, the reduction in signal transduction triggered by glucocorticoid receptor activation is utilized to identify glucocorticoid receptor modulators. Glucocorticoid receptor signaling activity can be measured in a number of ways. For example, signal transduction activity can be measured by monitoring downstream molecular events. Downstream events include activation or expression resulting from glucocorticoid receptor stimulation. Exemplary downstream events useful for functional assessment of transcriptional activation and antagonism in intact cells include increased expression of several glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). In addition, specific cell types susceptible to GR activation may be used, such as osteocalcin expression in osteoblasts, which is downregulated by glucocorticoids; and primary hepatocytes, which exhibit glucocorticoid-mediated increased expression of PEPCK and glucose-6-phosphate (G-6-Pase). GRE-mediated gene expression has also been demonstrated in transfected cell lines using well-known GRE regulatory sequences (e.g., the mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP), and chloramphenicol acetyltransferase (CAT). Functional assessment of transcriptional repression can be performed in cell lines such as monocytes or human dermal fibroblasts. Useful functional assays include measuring IL-1β-stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2, and various chemokines (MCP-1, Rantes); LPS-stimulated cytokine release, e.g., TNFα; or expression of genes regulated by NFkB or AP-1 transcription factors in transfected cell lines.

[0086] Compounds tested in whole cell assays can also be tested in cytotoxicity assays. Cytotoxicity assays are used to determine the extent to which a detected effect is due to a non-glucocorticoid receptor-binding cellular effect. In an exemplary embodiment, the cytotoxicity assay involves contacting constitutively active cells with the test compound. Any decrease in cellular activity is indicative of a cytotoxic effect.

[0087] Further illustrative of the many assays that can be used to identify compositions for use in the methods of the present invention are assays based on glucocorticoid activity in vivo. For example, an assay can be used to evaluate the ability of a putative GR modulator to inhibit the incorporation of 3H-thymidine into DNA in cells stimulated with glucocorticoids. Alternatively, a putative GR modulator can compete with 3H-dexamethasone in binding to GR in hepatoma tissue culture (see, e.g., Choi et al., Steroids, 57:313-318, 1992). Another example can utilize the ability of a putative GR modulator to block the nuclear binding of 3H-dexamethasone-GR complexes (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41:723-725, 1992). To further identify putative GR modulators, a kinetic assay can be used that can distinguish between glucocorticoid agonists and modulators by receptor binding kinetics (described in Jones, Biochem J., 204:721-729, 1982).

[0088] In another example, the assay described in Daune, Molec. Pharm., 13:948-955, 1977; and U.S. Patent No. 4,386,085 can be used to confirm antiglucocorticoid activity. Briefly, thymocytes from adrenalectomized rats are incubated in nutrient medium containing dexamethasone and various concentrations of the test compound (a putative GR modulator). 3H-uridine is added to the cell culture, further incubation is performed, and the extent of incorporation of the radiolabel into polynucleotides is measured. 3 GR modulators counter this effect by decreasing the amount of H-uridine.

[0089] The GR modulators selected above are then subjected to a selectivity assay to determine whether they are SGRMs. Typically, selectivity assays involve testing compounds that bind to glucocorticoid receptors in vitro for the degree of binding to proteins other than glucocorticoid receptors. Selectivity assays may be performed in vitro or in a cell-based system as described above. Binding may be tested against any suitable non-glucocorticoid receptor protein, including antibodies, receptors, enzymes, and the like. In an exemplary embodiment, the non-glucocorticoid receptor-binding protein is a cell surface receptor or a nuclear receptor. In another exemplary embodiment, the non-glucocorticoid receptor protein is a steroid receptor, such as an estrogen receptor, a progesterone receptor, an androgen receptor, or a mineralocorticoid receptor.

[0090] Various assays known to those skilled in the art can be used to measure the selectivity of an antagonist for GR relative to MR. For example, specific antagonists can be identified by measuring the binding ability of an antagonist to GR relative to MR (see, e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; and 5,071,773). Such analyses can be performed using direct binding assays or by assessing competitive binding to purified GR or MR in the presence of a known ligand. In an exemplary assay, cells stably expressing high levels of glucocorticoid receptor or mineralocorticoid receptor (see, e.g., U.S. Pat. No. 5,606,021) are used as a source of purified receptor. The affinity of the ligand for the receptor is measured directly. GR modulators that exhibit at least 10-fold, 100-fold, and often 1,000-fold higher affinity for GR relative to MR are selected for use in the methods of the present invention.

[0091] The selectivity assay may involve quantifying the ability to inhibit GR-mediated activity but not MR-mediated activity. One method for identifying such GR-specific modulators is to use a transfection assay to assess the ability of an antagonist to prevent the activation of a reporter construct (see, e.g., Bocquel et al., J. Steroid Biochem Molec. Biol., vol. 45:205-215, 1993; U.S. Patent Nos. 5,606,021 and 5,929,058). In an exemplary transfection assay, an expression plasmid encoding the receptor and a reporter plasmid containing a reporter gene linked to a receptor-specific regulatory element are cotransfected into suitable receptor-negative host cells. The transfected host cells are then cultured in the presence and absence of a hormone, such as cortisol or an analog thereof, that can activate the hormone-responsive promoter / enhancer element of the reporter plasmid. After transfection and culture, the host cells are then monitored for induction of production (i.e., the presence) of the reporter gene sequence. Finally, the expression and / or steroid-binding ability of hormone receptor proteins (encoded by receptor DNA sequences on expression plasmids and produced in host cells after transfection and culture) are measured by determining reporter gene activity in the presence and absence of antagonists. The antagonist activity of a compound may be determined in comparison with known antagonists of the GR and MR receptors (see, e.g., U.S. Pat. No. 5,696,127). Potency is reported as the percent maximal response observed for each compound compared to a reference antagonist compound. GR modulators that exhibit at least 100-fold, and often 1000-fold or more, activity against GR compared to MR, PR, or AR are selected for use in the methods disclosed herein.

[0092] One example of a non-steroidal SGRM that can be used in the methods disclosed herein is relacolinant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure: [ka]

[0093] Pharmaceutical Compositions and Administration In some embodiments, the present invention provides a pharmaceutical composition for treating hypercortisolism, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an SGRM. In a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a nonsteroidal SGRM.

[0094] GRMs and SGRMs (as used herein, GRMs and SGRMs include nonsteroidal GRMs and nonsteroidal SGRMs) can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Oral dosage forms include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. GRMs and SGRMs can also be administered by inhalation, for example, intranasally. Additionally, GRMs and SGRMs can be administered transdermally. Thus, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a GRM or SGRM.

[0095] When preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be either solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details regarding formulation and administration techniques are fully explained in the scientific and patent literature; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co., Easton, Pennsylvania ("Remington's").

[0096] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient, GRM or SGRM. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0097] Powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "formulation" is intended to encompass formulations of the active compound containing an encapsulating material as a carrier, with or without other carriers, surrounding the active ingredient, resulting in a capsule in which the carrier is associated with the active ingredient. Cachets and lozenges are also encompassed. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0098] Suitable solid pharmaceutical additives are carbohydrate or protein excipients, for example, but are not limited to: sugars such as lactose, sucrose, mannitol, or sorbitol; starches derived from plants such as corn, wheat, rice, or potato; celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums such as gum arabic and gum tragacanth; and proteins such as gelatin and collagen. If desired, disintegrants or solubilizers may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof (such as sodium alginate).

[0099] Dragee cores may be provided with a suitable coating, such as a concentrated sugar solution, which may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or dragee coating for product identification or to indicate the active compound content (i.e., dosage). The pharmaceutical formulations of the present invention can also be used orally, for example, in push-fit gelatin capsules and soft, sealed gelatin capsules, with a coating such as glycerol or sorbitol. Push-fit capsules may contain the GR modulator mixed with excipients or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the GR modulator may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0100] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution.

[0101] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water containing: viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; and dispersing or wetting agents such as natural phosphatides (e.g., lecithin), condensates of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensates of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensates of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The osmolarity of the preparations may be adjusted.

[0102] Also included are solid preparations, which are intended to be converted immediately before use into liquid preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0103] Oil suspensions can be formulated by suspending the SGRM in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Oil suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners can be added to make the preparation more palatable, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by adding an antioxidant such as ascorbic acid. For examples of injectable oily carriers, see Minto, J. Pharmacol. Exp. Ther., 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifying agents include natural gums such as gum arabic and gum tragacanth, natural phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain demulcents, preservatives, or coloring agents.

[0104] GRMs and SGRMs can be delivered transdermally and topically and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0105] GRMs and SGRMs can also be delivered as microspheres for sustained internal release. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for slow subcutaneous release (see Rao, J. Biomater Sci. Polym. Ed., Vol. 7: pp. 623-645, 1995); as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res., Vol. 12: pp. 857-863, 1995); or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol., Vol. 49: pp. 669-674, 1997). Both transdermal and intradermal routes allow for constant delivery over periods of weeks or months.

[0106] The pharmaceutical formulations of the present invention can be provided as salts, which can be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulations may be lyophilized powders in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH ranging from 4.5 to 5.5, and are combined with a buffer solution prior to use.

[0107] In another embodiment, the formulations of the present invention can be delivered using liposomes that fuse with the cell membrane, i.e., undergo endocytosis, by using a ligand attached to the liposome or directly attached to an oligonucleotide that binds to a cell surface membrane protein receptor, which then induces endocytosis. The use of liposomes allows for focused delivery of GR modulators to target cells in vivo, particularly if the liposome surface carries a ligand specific to the target cell or is otherwise preferentially targeted to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul., 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol., 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm., 46:1576-1587, 1989).

[0108] Pharmaceutical preparations are preferably in unit dosage form. In such a form, the preparation is subdivided into unit dosages containing an appropriate amount of GRM or SGRM as an active ingredient. This unit dosage form can be a packaged preparation, the package containing individual amounts of preparations, for example, tablets, capsules, and powders packaged in vials or ampoules. This unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in a packaged form.

[0109] The amount of active ingredient in a unit dose formulation can be varied or adjusted in the range of 0.1 mg to 10,000 mg, more typically 1.0 mg to 6,000 mg, and most typically 50 mg to 500 mg. Suitable dosages also include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg, depending on the particular application and potency of the active ingredient. The compositions can also contain other compatible therapeutic agents, if desired.

[0110] In some cases, an effective amount of a GRM (e.g., relacorilant) is a daily dose of 1-100 mg / kg / day, hi some embodiments, the daily dose of the GRM is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg / day. In some cases, the GRM is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 25 weeks, at least 30 weeks, at least 35 weeks, at least 40 weeks, at least 45 weeks, at least 50 weeks, at least 55 weeks, at least 60 weeks, at least 65 weeks, at least 70 weeks, at least 75 weeks, or at least 80 weeks.

[0111] Single or multiple administrations of the formulation can be administered based on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the pathological condition. Thus, in one embodiment, a pharmaceutical formulation for oral administration of GRM provides a daily dose of about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In some embodiments, the daily dose is about 1.0 to about 100 mg / kg / day, about 5 to about 50 mg / kg / day, about 10 to about 30 mg / kg / day, or about 10 to about 20 mg / kg / day. Lower doses can be used, particularly when the agent is administered to an anatomically isolated location, such as the cerebrospinal fluid (CSF) space, into the bloodstream, into a body cavity, or into the lumen of an organ, as opposed to oral administration. Significantly higher doses can be used for local administration. Actual methods for preparing formulations for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, "Receptor-Mediated Antisteroid Action," Agarwal et al. (eds.), De Gruyter, New York (1987).

[0112] The duration of treatment with a GRM or SGRM to reduce excess cortisol can vary depending on the severity of the subject's condition and the subject's response to the GRMs or SGRMs. In some embodiments, GRMs and SGRMs can be administered for a period of about 1 week to 104 weeks (2 years), more typically for a period of about 6 weeks to 80 weeks, and most typically for a period of about 9 weeks to 60 weeks. Suitable administration periods include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-104 weeks. Suitable administration periods include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, 100 weeks, and 104 weeks. Typically, administration of a GRM or SGRM should be continued until a clinically significant reduction or improvement is observed. Treatment with a GRM or SGRM according to the present invention may continue for as long as 2 years, or even longer.

[0113] In some embodiments, administration of a GRM or SGRM is not continuous, but can be separated by one or more withdrawal periods followed by one or more resumption periods. Suitable withdrawal periods include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 100 weeks. Suitable withdrawal periods also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, and 100 weeks.

[0114] The dosing regimen also takes into account pharmacokinetic parameters well known in the art, such as absorption rate, bioavailability, metabolism, and clearance (see, e.g., Hidalgo-Aragones (1996), J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996), Pharmazie 51:337-341; Fotherby (1996), Contraception 54:59-69; Johnson (1995), J. Pharm. Sci. 84:1144-1146; Rohatagi (1995), Pharmazie 50:610-613; Brophy (1983), Eur. J. Clin. Pharmacol. 24:103-108; Remington's, latest edition, supra). The current state of the art allows the clinician to determine the dosing regimen for each individual patient, GR modulator, and disease or condition being treated.

[0115] SGRMs can be administered in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvants that are not effective alone but may contribute to the efficacy of the active agent.

[0116] In some embodiments, co-administration includes administering one active agent, a GRM or an SGRM, within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, or about 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by combination, i.e., by preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuncts can be linked or complexed to each other.

[0117] Pharmaceutical compositions containing the GR modulators of the invention can be formulated in an acceptable carrier, placed in an appropriate container, and labeled for treatment of a designated condition. For administration of a GRM or SGRM, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0118] The pharmaceutical compositions of the present invention can be provided as salts, which can be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the formulation may be a lyophilized powder in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH ranging from 4.5 to 5.5, and combined with a buffer solution prior to use.

[0119] In another embodiment, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Formulations for administration typically comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents that can be used include water and Ringer's solution, an isotonic saline solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil can be used, including, for example, synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable solutions. These solutions are sterile and generally free of undesirable substances. These formulations may be sterilized by conventional, well-known sterilization methods. Pharmaceutically acceptable auxiliary substances may be included in the formulations to approximate physiological conditions, as needed, including, for example, pH adjusters, pH buffers, and toxicity adjusters, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the compositions of the present invention in these formulations can vary widely and will be selected primarily based on fluid volume, viscosity, body weight, and the like, according to the particular mode of administration selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0120] I. Combination Therapy Various combinations of a GRM or SGRM with another pharmaceutical agent (which may be a small molecule drug, a large molecule such as an antibody or peptide, an immunotherapeutic agent, a cancer chemotherapeutic agent, or a combination of such agents and compounds) may be used to treat a patient. The terms "combination therapy" or "in combination" are not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein. The GRM or SGRM and pharmaceutical agent may be administered according to the same or different dosing schedules. In some embodiments, the GRM or SGRM and pharmaceutical agent are administered sequentially in any order during all or part of the treatment period. In some embodiments, the GRM or SGRM and the other therapeutic agent are administered simultaneously or approximately simultaneously (e.g., within about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, or about 30 minutes of each other). Non-limiting examples of combination therapy, e.g., by administration of a GRM or SGRM with another therapeutic agent, are as follows, where the GRM or SGRM is designated "A" and the other therapeutic agent or compound given as part of the therapeutic regime is designated "B":

[0121] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0122] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0123] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A

[0124] Administration of therapeutic compounds or agents to patients will follow normal protocols for administering such compounds, taking into account the toxicity, if any, of the treatment. Surgical procedures may also be applied in combination with the described treatments.

[0125] The method can be combined with other therapeutic measures such as surgery, radiation, targeted therapy, immunotherapy, the use of growth factor inhibitors, or the use of anti-angiogenic factors.

[0126] All patents, patent publications, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. [Example]

[0127] The following examples are offered by way of illustration only, and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially similar results.

[0128] Example 1. HEPG2 tyrosine aminotransferase (TAT) assay The following protocol describes an assay for measuring the induction of TAT by dexamethasone in HepG2 cells (a human hepatocellular carcinoma cell line; ECACC, UK). HepG2 cells are cultured in MEME medium supplemented with 10% (v / v) fetal bovine serum, 2 mM L-glutamine, and 1% (v / v) NEAA at 37°C in 5% / 95% (v / v) CO2 / air. HepG2 cells are then counted and cultured at 0.125 x 10 in phenol red-free RPMI 1640, 10% (v / v) charcoal-stripped FBS, and 2 mM L-glutamine. 6 The density is adjusted to give 25,000 cells / ml and 200 μl is seeded into a 96-well sterile tissue culture microtiter plate at 25,000 cells / well and incubated at 37° C., 5% CO 2 for 24 hours.

[0129] Growth medium is then removed and replaced with assay medium (phenol red-free RPMI 1640, 2 mM L-glutamine + 10 μM forskolin). Test compounds are then screened against 100 nM dexamethasone. Compounds are then serially diluted in half-log in 100% (v / v) dimethylsulfoxide from a 10 mM stock. An 8-point half-log dilution curve is then generated, followed by a 1:100 dilution in assay medium to obtain 10x the final assay compound concentration, resulting in a range of final assay compound concentrations from 10 to 0.003 μM in 0.1% (v / v) dimethylsulfoxide.

[0130] Test compounds are pre-incubated with cells in microtiter plates for 30 minutes at 37°C in 5 / 95 (v / v) CO2 / air, followed by the addition of 100 nM dexamethasone, followed by 20 hours for optimal TAT induction.

[0131] Next, HepG2 cells are lysed with 30 μl of cell lysis buffer containing a protease inhibitor cocktail at 4°C for 15 minutes. Next, 155 μl of a substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM α-ketoglutaric acid, and 0.06 mM pyridoxal 5'-phosphate in 0.1 M potassium phosphate buffer (pH 7.4) can be added. After 2 hours of incubation at 37°C, the reaction can be terminated by adding 15 μl of 10 M aqueous potassium hydroxide solution. The plate can be incubated for an additional 30 minutes at 37°C. TAT activity products can be measured by absorbance at λ340 nm.

[0132] I C 50 IC values ​​can be calculated by plotting percent inhibition (normalized to 100 nM dexamethasone TAT stimulation) against compound concentration and fitting the data to a four-parameter logistic equation. 50 Values ​​can be converted to Ki (equilibrium dissociation constant) using the Cheng-Prusoff equation, assuming the antagonist is a competitive inhibitor with respect to dexamethasone.

[0133] Example 2. Clinical response to relacolinant Response to relacolinant in healthy subjects Studies of relacorilant in human volunteers have shown that daily administration achieves steady-state levels by day 7. Single doses of relacorilant from 5 mg to 500 mg were well tolerated in human subjects, as were relacorilant doses of 50 mg, 150 mg, and 250 mg administered over a 14-day period. Mild to moderate musculoskeletal AEs were reported in some subjects with repeated doses up to 250 mg. Transient platelet count decreases were observed in some subjects in a non-dose-dependent manner, which resolved by study completion. Additionally, some subjects received 500 mg of relacorilant. Non-serious musculoskeletal adverse events were reported in some subjects.

[0134] Example 3. Clinical response to relacolinant Response to relacorilant in patients with Cushing's syndrome. Relacorilant was administered orally (or self-administered) once daily (in the morning, without food for 4 hours before and 1 hour after administration) to male and female fasting Cushing's syndrome patients (n=35) (50 mg of each capsule). These patients had a confirmed diagnosis of endogenous Cushing's syndrome and at least one of the following: a) type 2 diabetes or impaired glucose tolerance, and b) uncontrolled or untreated hypertension. Informed consent was obtained from all patients before participation in any study-related procedures.

[0135] Patients received an initial dose of relacorilant daily for 4 weeks, then increased the daily dose by 50 mg every 4 weeks as tolerated. The first 17 enrolled patients (Group 1, "Low-Dose Cohort," LD) received 100 mg relacorilant / day for 4 weeks, then 150 mg relacorilant / day for 4 weeks, then 200 mg relacorilant / day for 4 weeks (total 12 weeks). The next 18 patients (Group 2, "High-Dose Cohort," HD) started at 250 mg relacorilant / day, increasing this to 300 mg relacorilant / day after 4 weeks, then 350 mg relacorilant / day after 4 weeks, and finally, if tolerated, at 350 mg / day for 4 weeks, followed by 400 mg relacorilant / day for the final 4 weeks (total 16 weeks).

[0136] The study protocol required patients to visit the study site at screening, on Day 1 (baseline), at Weeks 2, 4, 6, 8, 10, and 12, and after a 4-week follow-up period for Group 1. For Group 2, the protocol required patients to visit the study site at screening, on Day 1 (baseline), at Weeks 2, 4, 6, 8, 10, 12, 14, and 16, and after a 4-week follow-up period. Patient dosing will be performed at home except on study visit days.

[0137] Patient monitoring during the study included monitoring blood levels of relacorilant and its metabolites, with measurements taken pre-dose and 1, 2, 4, 6, and 8 hours after dosing at Weeks 2, 6, and 10, and pre-dose only / early withdrawal (ET) at Weeks 4, 8, and 12 (for patients in Group 1). For patients in Group 2, blood levels of relacorilant and its metabolites were taken pre-dose and 1, 2, 4, 6, and 8 hours after dosing at Weeks 2, 6, 10, and 14, and pre-dose only / early withdrawal (ET) at Weeks 4, 8, 12, and 16. The safety protocol also included physical examination findings, vital signs, ECG results, pregnancy test, clinical laboratory results (hematology and chemistry panel), adverse events (AEs), and assessment of concomitant medications. Safety and pharmacokinetic (PK) data were reviewed to confirm the appropriateness of the administered dose level, including after high-dose escalation (i.e., 2 weeks after dose escalation to 200 mg / day), when steady-state PK data were available in the six patients who reached the highest relacorilant dose (e.g., Week 10 for the 350 mg relacorilant daily dose and Week 14 for the 400 mg relacorilant daily dose), and at the end of the study.

[0138] Response criteria for hyperglycemia were a change from baseline in glucose tolerance, as determined by a ≥0.5% decrease in HbA1c, normalization or a ≥50 mg / dL decrease in 2-hour OGTT glucose, or a reduction in total daily dose of insulin (≥25%) or sulfonylurea (≥50%).Response criteria for hypertension (HTN) were a ≥5 mmHg decrease in mean systolic and / or mean diastolic blood pressure (SBP / DBP).

[0139] In this study, for the high-dose cohort (Arm 2), 50% of patients with hyperglycemia achieved improved glucose control as indicated by (i) a 0.5% or greater reduction in HbA1c, or (ii) normalization of 2-hour oGTT glucose or a reduction of at least 50 mg / dL, or (iii) a 25% reduction in antidiabetic medication. 64% of patients with uncontrolled hypertension achieved a 5-millimeter or greater reduction in systolic or diastolic blood pressure as measured by 24-hour ambulatory monitoring. Patients in the high-dose group also met a wide range of secondary endpoints, including statistically significant improvements in hypercoagulopathy, liver function, serum osteocalcin (a marker of bone formation), cognitive function, depression, and quality of life.

[0140] Therapeutic improvements noted in at least some patients include: improvement in blood clotting, indicating improvement in hypercoagulability and reduced risk of embolism; improvement in other blood indices (e.g., platelet count, etc.); improvement in indices of heart function and heart rhythm (e.g., improvement in abnormal heart function, improvement in indices of left ventricular hypertrophy); improvement in measures of liver function; improvement in measures of immune system function and status; improvement in the degree of bone health; improvement in the patient's quality of life; improvement in the patient's psychological well-being (e.g., alleviation of depression); and improvement in the patient's glucose levels, indicating improvement or reduced risk of metabolic syndrome, pre-diabetes, or diabetes.

[0141] These and further results are shown in Table 1.

[0142] Relacorilant was well tolerated by these patients. There was no evidence that relacorilant had progesterone receptor affinity; none of the patients developed hypokalemia. There were no drug-related serious adverse events.

[0143] Figure 1 shows the improvement in glucose control resulting from administration of relacorilant. 50% of hyperglycemic patients in the high-dose cohort achieved improved glucose control (see Figure 1). The response rate in hypertensive patients was 64% (see Figure 2). These response rates are comparable to the response rates seen in patients at week 16 and with the 1200 mg dose in Korlym's pivotal studies (e.g., Fleseriu et al., J. Clin. Endocrinol. Metab., 97(6):2039-2049 (2012); Fleseriu et al., J. Clin. Endocrinol. Metab., 99(10):3718-3727 (2014)).

[0144] The clinical results of the study are shown in Table 1. Results are reported for the modified intent-to-treat (mITT) and modified per-protocol (mPP) populations; the intent-to-treat (ITT) analysis includes all subjects randomized according to random treatment assignment. It ignores non-compliance, protocol deviations, discontinuations, and anything that occurs after randomization. In contrast, the per-protocol (PP) analysis refers to the inclusion of only patients who strictly adhered to the protocol. The PP analysis provides an assessment of the true efficacy of the intervention, i.e., efficacy in patients who completed treatment as planned. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0145] These results indicate that AUC グルコースThe study demonstrated a statistically significant reduction in hypertension. The response rates were 15.4% in the LD group and 50% in the HD group by weeks 12 and 16, respectively. The response rates for hypertension were 41.7% in the LD group and 63.6% in the HD group by weeks 12 and 16, respectively. In addition to these primary endpoints, significant changes were also observed in various secondary endpoints related to hypercortisolism, including improvements in hypercoagulability, liver function, insulin sensitivity, cognitive function, depression, and Cushing's disease quality of life (QoL) scores. Some weight loss was observed in many patients. The most common treatment-emergent adverse events (TEAEs) were back pain, edema, headache, and nausea. Five serious TEAEs were reported in four patients. All of these serious TEAEs occurred in the HD group and are primarily related to the exacerbation of chronic conditions suppressed by chronic hypercortisolism. Neither drug-induced hypokalemia nor vaginal bleeding was observed in this study.

[0146] These results indicate that lelacorilant is useful in reducing many of the effects of excess cortisol in patients with Cushing's syndrome. Thus, lelacorilant treatment may be useful in treating Cushing's syndrome. Additionally, lelacorilant may be useful in treating fatty liver disease (see, e.g., ALT, AST, HOMA, and other measures in Table 1). Furthermore, lelacorilant may be useful in treating bone disorders (see, e.g., serum osteocalcin measure in Table 1). Lelacorilant may also be useful in treating heart disease, including left ventricular hypertrophy, arrhythmias, and other forms of heart disease (see, e.g., cardiac measures such as QT in Table 1). Additionally, lelacorilant may be useful in treating blood clotting disorders, depression, and improving patient quality of life. Lelacorilant may be useful in combination with immunotherapeutic agents, such as checkpoint inhibitors, as well as in diagnostic testing.

[0147] These results demonstrate that doses of up to 400 mg / day of relacorilant demonstrated clinical improvements in hyperglycemia and hypertension, as well as improvements in other endpoints related to cortisol excess. Relacorilant was generally well tolerated. It provides the clinical benefits of potent glucocorticoid modulation without the undesirable effects mediated by antiprogestational or antimineralocorticoid (cortisol-increasing) properties.

[0148] GR antagonism is a clinically validated treatment for Cushing's syndrome The first trial of relacorilant in patients with Cushing's syndrome (CORT125134-451; NCT02804750) enrolled a total of 35 patients at 19 centers in the United States, Italy, the United Kingdom, Hungary, and the Netherlands.

[0149] Twenty-eight patients (80%) had adrenocorticotropic hormone (ACTH)-dependent causes of Cushing's syndrome (pituitary or ectopic), and 7 patients (20%) had adrenal causes of Cushing's syndrome. The efficacy of the above drugs in Cushing's syndrome was evaluated based on the improvement of pathological conditions associated with excess cortisol activity, such as hyperglycemia, hypertension, cognitive impairment, depression, poor quality of life, hypercoagulopathy, and obesity. (Pathological conditions associated with excess cortisol, such as hypercortisolemia, Cushing's syndrome, Cushing's disease, etc., are also referred to as "complications.")

[0150] Consistent with the expected dose effect, 2 / 13 (15.4%) hyperglycemic patients treated with doses up to 200 mg and half (6 / 12) of those treated with doses up to 400 mg demonstrated strong evidence of glycemic improvement. Response was based on a ≥0.5% decrease in HbA1c associated with a reduction or discontinuation of antidiabetic medication or a clinically significant decrease (≥50 mg / dL) or normalization of 2-hour glucose measurements obtained from an oral glucose tolerance test (OGTT). Among patients with uncontrolled hypertension, 5 / 12 (41.7%) patients receiving doses up to 200 mg per day and 7 / 11 (63.6%) patients receiving doses up to 400 mg per day demonstrated clinically significant improvements (≥5 mmHg decrease) in 24-hour mean systolic and diastolic blood pressure measured by 24-hour ambulatory blood pressure monitoring. These patients also demonstrated clinically significant improvements in nocturnal and daytime blood pressure. This clinical improvement was observed without the development of drug-induced hypokalemia, a common adverse event in patients treated with mifepristone or metyrapone. Also, as expected, patients treated with relaxorilant did not experience the adverse effects of progesterone receptor antagonism, an added advantage over mifepristone.

[0151] In addition to the improvements in hyperglycemia and hypertension typically observed within two weeks of achieving a therapeutic dose of relacorilant, significant improvements were also observed in several other cortisol-related complications, as shown in Table 2 below. [Table 2]

[0152] Although greater weight loss is typically observed with longer treatment with GR antagonists, significant weight changes were observed within 3 months in half of the patients in the relacorilant study, with a mean weight loss of 2.2 kg in patients treated with doses up to 200 mg / day and 5.1 kg in patients treated with doses up to 400 mg / day.

[0153] Improvement / normalization of abnormal increases in clotting factors due to excessive cortisol activity was observed as early as 1 month after relacorilant treatment. This contrasts with findings after curative surgery in patients with pituitary Cushing's syndrome, where clotting factors begin to decrease 3 months after surgery and often remain elevated for at least 6 months after surgery (Trementino et al., Neuroendocrinology, Vol. 92, Suppl. 1: pp. 55-59 (2010)). Given the increased risk of thrombotic events in patients with hyperactive Cushing's syndrome after curative surgery, relacorilant may even be an option for preoperative coagulation control in patients at high risk for intraoperative and postoperative thrombotic events.

[0154] In patients with adrenal Cushing's syndrome, reversal of hypothalamic-pituitary-adrenal (HPA) axis suppression was observed in half of cases, even in patients with severe Cushing's syndrome who had previously received chronic metyrapone therapy. HPA axis recovery, based on restoration of ACTH secretion and, in some cases, restoration of cortisol circadian rhythm, was observed within 2 to 6 weeks of relacorilant treatment. This is an important finding, and there are at least two reasons for this emphasis: A) It demonstrates the rapid beneficial effects of relacorilant in patients with hypercortisolism. HPA axis recovery after curative surgery typically takes several months, and in some cases, several years. B) It serves as a marker for dose titration, similar to thyroid-stimulating hormone (TSH) in patients with hyperthyroidism and plasma renin activity in patients with primary aldosteronism.

[0155] The safety profile of relacorilant in patients with endogenous Cushing's syndrome was also significantly more favorable than that observed with mifepristone. Unlike the adverse events of mifepristone related to progesterone receptor antagonism, no cases of drug-induced vaginal bleeding were observed in the relacorilant study, even among patients who had previously experienced vaginal bleeding while taking mifepristone. Equally important, no patients developed drug-induced hypokalemia, even those who had previously experienced hypokalemia while taking mifepristone. The most common treatment-emergent adverse events (TEAEs) were back pain, edema, headache, and nausea.

[0156] In the Phase 2 CORT125134-451 trial of relacorilant, five patients previously treated with other approved medical therapies were enrolled after tapering or discontinuing their medications. These patients had either a partial response or experienced adverse events to these other therapies. Two patients had previously received metyrapone, two had previously received ketoconazole, and one had previously received mifepristone. In both patients previously treated with metyrapone, relacorilant demonstrated greater efficacy based on improvements in the primary endpoints of glucose control and hypertension, as well as secondary endpoints including weight loss and HPA axis restoration. The patient previously treated with mifepristone had endometrial hyperplasia, which completely resolved during relacorilant treatment.

[0157] Relacorilant was rationally designed to be a selective GR antagonist and not bind to other nuclear steroid hormone receptors. Relacorilant's GR selectivity, and in particular its lack of binding to the progesterone receptor, provides a significant safety advantage over mifepristone. To date, two common TEAS (vaginal bleeding or hypokalemia) reported with mifepristone have not been reported with relacorilant.

[0158] Although the invention has been described above in some detail by way of illustration and example for clarity of understanding, those skilled in the art will readily appreciate that certain changes and modifications can be made in light of the teachings of the invention without departing from the spirit and scope of the appended claims. The present invention also includes the following aspects. <1> 1. A method of treating a patient having hypercortisolism and its symptoms or complications, comprising: Administering to a subject an effective amount of a non-steroidal selective glucocorticoid receptor modulator (selective GRM) having a heteroaryl-ketone fused azadecalin structure or a non-steroidal selective GRM having an octahydro-fused azadecalin structure, a method effective for treating the symptoms or complications of hypercortisolism, The symptoms or complications of hypercortisolism are: The treatment is performed on the patient's baseline AUC measured before treatment. グルコース AUC of patients compared to グルコース is effective in significantly reducing hyperglycemia; hypertension, wherein the treatment is effective in significantly lowering the patient's blood pressure when compared to the patient's baseline blood pressure measured before treatment; abnormal liver enzyme levels, wherein said treatment is effective to significantly reduce the abnormal liver enzyme levels in the patient when compared to the patient's baseline liver enzyme levels measured prior to treatment; an abnormality in fructosamine levels, wherein the treatment is effective to significantly improve the abnormality in the patient's fructosamine levels when compared to the patient's baseline fructosamine levels measured before treatment; an abnormality in serum osteocalcin levels, wherein the treatment is effective to significantly improve the abnormality in the patient's serum osteocalcin levels when compared to the patient's baseline serum osteocalcin level measured before treatment; an abnormality in beat-to-beat interval or median heart rate, wherein the treatment is effective to significantly improve the abnormality in the patient's beat-to-beat interval or median heart rate when compared to the patient's baseline beat-to-beat interval or median heart rate measured before treatment; a blood coagulation abnormality, wherein the treatment is effective to significantly improve the patient's blood coagulation abnormality when compared to the patient's baseline blood coagulation measured before treatment; a blood cell degree abnormality, wherein the treatment is effective to significantly improve the patient's blood cell degree abnormality when compared to the patient's baseline blood cell degree measured before treatment; an abnormality in an adrenocorticotropic hormone (ACTH) or proopiomelanocortin (POMC) level, wherein the treatment is effective to significantly improve the abnormality in the patient's ACTH or POMC level when compared to the patient's baseline ACTH or POMC level measured before treatment; 1. A method for treating Cushing's disease in a patient, wherein the treatment is effective in significantly improving the patient's quality of life when compared to the patient's baseline quality of life measured before treatment. improving quality of life for patients; improving cognition in Cushing's patients, wherein the treatment is effective to significantly improve the patient's cognition when compared to the patient's baseline cognition measured prior to treatment; alleviating depression in the patient, wherein the treatment is effective to significantly reduce the patient's depression as measured by a psychological measure of depression when compared to the patient's baseline depression measured before treatment; one or more of A method for treating a patient suffering from hypercortisolism and its symptoms or complications, wherein said symptoms or complications are ameliorated. <2> the symptom or complication is hyperglycemia, and the treatment is effective in improving the patient's glucose control as compared to the patient's baseline glucose control measured prior to treatment. <1> The method described below. <3> the symptom or complication is hyperglycemia, and the treatment is effective to reduce the patient's hemoglobin A1c (HbA1c) by at least about 0.5% as compared to the patient's baseline HbA1c measured before treatment. <1> The method described below. <4> and wherein the symptom or complication is hyperglycemia, and the treatment reduces the patient's baseline AUC measured before treatment. グルコース AUC of patients compared to グルコース effective to reduce by at least about 15% <1> The method described below. <5> the condition or complication is hypertension, and the treatment is effective to reduce the patient's 24-hour mean systolic blood pressure or 24-hour mean diastolic blood pressure by at least about 5 millimeters of mercury (mmHg) when compared to the patient's baseline blood pressure measured before treatment. <1> The method described below. <6> the symptom or complication is an abnormality in heart beat interval or median heart rate, and the treatment is effective in significantly improving the abnormality in the patient's heart beat QT interval or median ECG heart rate when compared to the patient's baseline heart beat QT interval or median ECG heart rate measured before treatment. <1> The method described below. <7> the symptom or complication is abnormal liver enzyme levels, and the treatment is effective in significantly reducing the patient's alanine aminotransferase (ALT) liver enzyme level or aspartate aminotransferase (AST) liver enzyme level, or both, when compared to the patient's baseline ALT liver enzyme level or aspartate aminotransferase (AST) liver enzyme level measured before treatment. <1> The method described below. <8> the symptom or complication is an abnormal fructosamine level, and the treatment is effective to significantly improve the abnormal fructosamine level in the patient when compared to the patient's baseline fructosamine level measured before treatment. <1> The method described below. <9> the symptom or complication is an abnormality in osteocalcin levels, and the treatment is effective to significantly improve the abnormality in the patient's osteocalcin levels when compared to the patient's baseline osteocalcin levels measured before treatment. <1> The method described below. <10> the symptom or complication is an abnormality in blood coagulation factor levels, and the treatment is effective in significantly improving the abnormality in factor IX levels or abnormality in factor X levels when compared to the patient's baseline factor IX or factor X levels measured before treatment. <1> The method described below. <11> the symptom or complication is an abnormality in the degree of blood coagulation, and the treatment is effective in significantly improving the abnormality in thrombin-antithrombin (ATT) or activated partial thromboplastin time (aPTT) when compared to the patient's baseline ATT or aPTT measured before treatment. <1> The method described below. <12> the symptom or complication is a blood cell quantity abnormality selected from an abnormal eosinophil level or an abnormal platelet count, and the treatment is effective to significantly improve the patient's eosinophil level abnormality or platelet count abnormality when compared to the patient's baseline eosinophil level or platelet count abnormality measured before treatment; <1> The method described below. <13> the condition or complication is an abnormality in adrenocorticotropic hormone (ACTH) levels or proopiomelanocortin (POMC) levels, and the treatment results in an increase in the patient's ACTH levels when compared to the patient's baseline ACTH or POMC levels measured before treatment. The method is effective in significantly improving abnormalities in BP1 or POMC levels. <1> The method described below. <14> the symptom or complication is a decreased quality of life in a Cushing's patient, and the treatment is effective in significantly improving the patient's quality of life as measured by a Cushing's Quality of Life Score compared to the patient's baseline quality of life as similarly measured before treatment. <1> The method described below. <15> the symptom or complication is cognitive decline in a Cushing's patient, and the treatment is effective in significantly improving the patient's cognition as measured by cognitive testing compared to the patient's baseline cognition as measured by the cognitive testing prior to treatment; <1> The method described below. <16> The cognitive test is a trail making test. <15> The method described below. <17> the symptom or comorbidity is depression as assessed by the Beck Depression Scale, and the treatment is effective in significantly reducing the patient's depression as measured by the Beck Depression Scale compared to the patient's baseline depression similarly measured prior to treatment. <1> The method described below. <18> The nonsteroidal selective glucocorticoid receptor modulator (selective GRM) is relacorilant, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the formula:

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Claims

1. 1. A composition for treating a patient suffering from hypercortisolism comprising an effective amount of relacorilant, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the formula: 【Chemistry 1】 10. The method of claim 1, wherein said treating comprises administering to said patient: a reduction in liver enzyme levels, wherein the patient's alanine aminotransferase (ALT) levels are reduced by at least 10.6 units / L (U / L) when compared to the patient's baseline ALT levels measured before treatment, or the patient's aspartate aminotransferase (AST) levels are reduced by at least 4.9 units / L (U / L) when compared to the patient's baseline AST levels measured before treatment; a reduction in the patient's beat-to-beat QT interval by at least 13.6 milliseconds (msec) when compared to the patient's baseline beat-to-beat QT interval measured before treatment; an improvement in a blood coagulation measure in the patient when compared to the patient's baseline blood coagulation measure measured before treatment, said improvement comprising: the patient's blood clotting measurement is selected from at least a 22% reduction in Factor IX (%) or at least an 18% reduction in Factor X (%) when compared to the patient's baseline blood clotting measurement taken before treatment; The composition provides one or more of the following:

2. The composition described in claim 1, wherein the treatment results in a reduction in the heart rate interval in the patient.

3. The composition described in claim 1, wherein the treatment results in a decrease in the liver enzyme levels in the patient.

4. The composition described in claim 1, wherein the treatment results in an improvement in the blood coagulation measurements in the patient.

5. The composition of claim 1 for oral administration.

6. 10. The composition of claim 1 for administration without food.

7. 10. The composition of claim 1 for administration with food.

8. 2. The composition according to claim 1, wherein the effective amount is 1 to 100 mg / kg / day as a daily dose of relacorilant.

9. 10. The composition of claim 1, wherein the composition is administered daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or at least 20 weeks.

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