Amorphous solid dispersion of tildacerfont formulations

Abstract

Provided are amorphous solid dispersions (ASD) of a compound of Formula I. Also provided herein is a method of making the amorphous solid dispersion.

Description

AMORPHOUS SOLID DISPERSION OF TILDACERFONT FORMULATIONSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 563,111 filed March 8, 2024, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Tildacerfont is an antagonist of corticotropin releasing factor (CRF), which can be a useful therapeutic agent for treating congenital adrenal hyperplasia (CAH).

[0003] Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH affects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: 1) glucocorticoids, which gauge the body's response to stress, illness, or injury; 2) mineralocorticoids, which regulate salt and water levels; and 3) androgens, which are male sex hormones. An enzyme deficiency may make the body unable to produce one or more of these hormones, which in turn may result in the overproduction of another type of hormone precursor in order to compensate for the loss.

[0004] Congenital Adrenal Hyperplasia (CAH) patients need adequate care and treatment in order to lead normal lives. Hence, there is a need for new methods of treating CAH. This disclosure provides new compounds, salts, compositions and uses thereof in the treatment of CAH.

[0005] Tildacerfont was previously synthesized in a stable crystalline form, which can cause solubility issues during formulation. This is problematic as low solubility can lead to poor bioavailability and inconsistent drug absorption, which can affect the drug's efficacy.

[0006] A solution to improve the solubility of tildacerfont is to use a substantially noncrystalline form, i.e., an amorphous form of tildacerfont. Amorphous forms lack a crystalline structure, which may be useful for having greater solubility and dissolution rates than their crystalline forms. This can lead to better bioavailability and consistent drug absorption.SUMMARY

[0007] In some aspects is a composition comprising a polymer matrix and a compound of Formula I:wherein the compound of Formula I is present in a form that is substantially non-crystalline.

[0008] In some embodiments, the polymer matrix is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof. In some embodiments, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit LI 00-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit S100, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit LI 00 -55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit LI 00-55, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M.

[0009] In some embodiments, the composition further comprises a surfactant. In some embodiments, the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof. In some embodiments, the surfactant is Kolliphor RH40, TPGS, or a combination thereof. In some embodiments, the surfactant is TPGS.

[0010] In some embodiments, the polymer matrix is HPMCAS M and the surfactant is TPGS.

[0011] In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 10:90 to 50:50. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to 40:60. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to 30:70. In some embodiments further comprising a surfactant, wherein the ratio of the compound of Formula I, polymer matrix, and surfactant is in a ratio of about 25:65:10.

[0012] In some embodiments, the composition has a bioavailability of greater than 50% . In some embodiments, the composition has a bioavailability of greater than 75%. In some embodiments, the composition has a bioavailability of greater than 90%.

[0013] In some aspects is a method of making an amorphous solid dispersion (ASD), wherein the amorphous solid dispersion comprises a polymer matrix and a compound of Formula I:wherein the method comprises mixing a compound of Formula I with a polymer matrix in a buffer solution.

[0014] In some embodiments, the compound of Formula I is present in a form that is substantially not crystalline.

[0015] In some embodiments, the buffer solution is phosphate buffer. In some embodiments, the phosphate buffer is 50 mM phosphate buffer pH 6.8 with 1.0% Tween 80.

[0016] In some embodiments, the compound of Formula I and the polymer matrix is first dissolved in an organic solvent. In some embodiments, the organic solvent is tetrahydro furan, dichloromethane, methanol, ethanol, or acetone. In some embodiments, wherein the organic solvent is removed, and the buffer solution is added.

[0017] In some embodiments, the method has features as described in the embodiments above.

[0018] In some aspects is a compound of Formula I,wherein the compound is prepared from a stable crystalline form, wherein the form of the compound of Formula I in a composition is substantially non-crystalline.

[0019] In some embodiments, wherein the crystalline form is dissolved in an organic solvent with a polymer matrix to form the compound of Formula I, which is substantially non-crystalline. In some embodiments, the organic solvent is tetrahydrofuran, dichloromethane, methanol, ethanol, or acetone. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, or a combination thereof.

[0020] In some aspects is a composition comprising a polymer matrix and a compound of Formula II:RAs pB — R N^p4Formula (II) wherein:RAis Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5-to 12- membered heterocyclyl, optionally substituted C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, and 5- to 12- membered heteroaryl is optionally substituted with one or more Ci.C6alkyl;RBis hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5-to 12- membered heterocyclyl, C6-Ci2aryl, and 5-to 12- membered heteroaryl is optionally substituted with halogen, Ci.C6alkyl, or Ci-Ce alkoxy;R4is hydrogen, halogen, Ci-C6alkyl, -NR4aR4b,-NHC(O)Ci-C6alkyl, -Ci-C6alkylene-O-Ci- C6alkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5-to 6- membered heteroaryl is optionally substituted with Ci-Ce alkyl; andR4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with oneor more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, optionally substituted C3- C6cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6- Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl; wherein the compound of Formula II is present in a form that is substantially not crystalline.

[0021] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Il-a):Formula (Il-a) wherein:R1and R2are independently ethyl or w-propyl;R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;R4is hydrogen, Br, -NR4aR4b, meth oxy methyl, w-butyl, acetamido, pyridin-4-yl, morpholin-R4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-Cealkyl, -C(O)OCi-Cealkyl, C3-Cecycloalkyl, 5 - to 12- membered heterocyclyl, Ce-Ci2aryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl.

[0022] In some embodiments, R3is F, Cl, Br, methyl, or trifluoromethyl. In some embodiments, R3is Cl or Br.CH3L „N, N

[0023] In some embodiments, R4is -NRaRb, pyridin-4-yl, morpholin-4-yl, or ' N' _UCH3L „N, NIn some embodiments, R4is morpholin-4-yl or ' N' _U In some embodiments, R4is -NRaRb, and Raand Rbare independently Ci-C3alkyl.

[0024] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the composition has a feature as described in the embodiments above.

[0028] In some aspects is a method of treating congenital adrenal hyperplasia (CAH), the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0029] In some aspects is a method of treating testicular adrenal rest tumors (TART) or ovarian adrenal rest tumors (OART), the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0030] In some aspects is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0031] In some aspects is a method of treating a neurological disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition. In some embodiments, the neurological disease or disorder is depression.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 illustrates a differential scanning calorimetry (DSC) measurement taken of pure crystalline SPN-001.

[0033] FIG. 2 illustrates the X-ray powder diffraction (XRPD) of the pure crystalline SPN-001.

[0034] FIG. 3 illustrates modeling of miscibility between SPN-001 and different polymer excipients.

[0035] FIG. 4 illustrates SPN-001 microevaporative screening.

[0036] FIG. 5 illustrates SPN-001 microevaporative screening with surfactants.

[0037] FIG. 6 illustrates the X-ray powder of amorphous SPN-001 with HPMCAS M in a 30:70 ratio.

[0038] FIG. 7 illustrates the X-ray powder of amorphous SPN-001 : HPMCAS M: TPGS in a ratio of 25:65:10.

[0039] FIG. 8 illustrates the mean plasma concentration-time profiles of SPN-001 following intravenous administration at 1 mg / kgand oral administrations at 50 mg / kgto male Sprague Dawley rats.

[0040] FIG. 9 illustrates the mean plasma concentration -time profiles of SPN-001 following intravenous administration at 2 mg / kg and oral administrations at 20 mg / kg in dogs.DETAILED DESCRIPTION

[0041] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.Congenital adrenal hyperplasia

[0042] Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH effects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: 1) glucocorticoids, which gauge the body's response to stress, illness or injury; 2) mineralocorticoids, which regulate salt and water levels; and 3) androgens, which are male sex hormones. An enzyme deficiency will make the body unable to produce one or more of these hormones, which in turn will result in the overproduction of another type of hormone precursor in order to compensate for the loss.

[0043] The most common cause of CAH is the absence of the enzyme 21 -hydroxylase. Different mutations in the gene responsible for 21 -hydroxylase result in different levels of the enzyme, producing a spectrum of effects. CAH due to 21 -hydroxylase deficiency is responsible for 95% of all cases of CAH and is broken down further into two subcategories: classic CAH, which can be sub-divided into the salt-losing form or the simple-virilizing form, and non-classic CAH. Classic CAH is by far the more severe form and can result in adrenal crisis and death if not detected and treated. Non-classic CAH is milder and may or may not present symptoms. Since the absence of 21 -hydroxylase makes these individuals unable to make the hormone cortisol, a glucocorticoid, and, in the case of salt-losing CAH, aldosterone (a mineralocorticoid), the excess steroid precursors, namely 17 -hydroxyprogesterone (17- OHP), build up and are shunted down the androgen pathway resulting in excess androgen production which cause a variety of symptoms such as abnormal genital development in infant girls. There are other much rarer forms of CAH as well, including 11 -13 hydroxylase deficiency, 17a-hydroxylase deficiency, 3 -13-hydroxy steroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia andp450 oxidoreductase deficiency which all present different symptoms. CAH patients need adequate care and treatment in order to lead normal lives.Corticotropin releasing factor

[0044] Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors.

[0045] CRF has been implicated in psychiatric disorders and neurological diseases including depression and anxiety, as well as the following: Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol and substance abuse and associated withdrawal symptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia (CAH), Cushing's disease, hypertension, stroke, irritable bowel syndrome, stress -induced gastric ulceration, premenstrual syndrome, sexual dysfunction, premature labor, inflammatory disorders, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary tumors or ectopic pituitary derived tumors, chronic fatigue syndrome, and fibromyalgia.

[0046] CRF receptor subtypes, CRF1 and CRF2, have been identified and are distributed heterogeneously within the brain thereby suggesting potential functional diversity. For example, widely distributed brain CRF1 receptors are strongly implicated in emotionality accompanying exposure to environmental stressors. Significantly, CRF1 , not CRF2, receptors appear to mediate select anxiogenic like behaviors.

[0047] Treatment of CAH is based on normalization of hormone and steroid levels using a variety of chronic medications from diagnosis in infancy through adulthood.Glucocorticoids are the current standard treatment in CAH and are used both to correct the endogenous Cortisol deficiency and for reducing the elevated ACTH levels from the pituitary, which drives increased androgen production. Unlike the treatment of Addison's disease (adrenal insufficiency), in which Cortisol replacement is sufficient, the treatment of CAH must also reduce ACTH production, to control the subsequent androgen excess as well. Thus, the goals of glucocorticoid treatment include cortisol replacement and suppression of ACTH to prevent virilization and menstrual disturbances in women. Mineralocorticoid replacement is needed to achieve normal plasma renin activity for maintenance of regularblood pressure, electrolyte balance, and volume status in those patients with the salt -wasting form of CAH.

[0048] The regimen of glucocorticoid treatment must support normal physiology and also ensure that sufficient cortisol is available during events that may elicit a strong stress response (e.g., intercurrent illness, exercise, hypotension). Careful monitoring is also necessary to avoid the development of Addisonian syndrome due to under -treatment. Overtreatment with mineralocorticoids may cause hypertension while under-treatment may lead to low blood pressure, salt loss, fatigue and increased requirements for glucocorticoids. Typical laboratory tests for monitoring treatment efficacy include measurement of plasma concentrations of 17-OHP, androstenedione (A4), testosterone, renin activity, and electrolytes.

[0049] Adult patients with CAH have an increased prevalence of risk factors for cardiovascular disease including obesity, hypertension, absence of the nadir drop in systolic blood pressure overnight, and insulin resistance. A study of a large cohort of pediatric and adult CAH patients (n=244) demonstrated that patients are prescribed a variety of glucocorticoid treatment regimens yet frequently suffer from poor hormonal control and the aforementioned adverse outcomes. Treatment of CAH includes efforts to normalize the Cortisol deficiency with glucocorticoids (usually hydrocortisone in children and adults). In some embodiments, there is a need for longer acting and more potent agents with narrow therapeutic indices, such as dexamethasone or prednisolone / prednisone, in adults and, if necessary for salt-wasting, mineralocorticoids (usually fludrocortisone). The glucocorticoid doses required to achieve sufficient suppression of excess androgens, however, are usually well above the normal physiologic dose used for cortisol replacement alone as in patients with Addison's disease. This increased exposure to glucocorticoids can lead to increased cardiovascular risk factors, glucose intolerance, and decreased bone mineral density in CAH patients.

[0050] CRF is believed to be the major physiological regulator of the basal and stress- induced release of adrenocorticotropic hormone ("ACTH"), P -endorphin, and other proopiomelanocortin ("POMC")-derived peptides from the anterior pituitary. Secretion of CRF causes release of ACTH from corticotrophs in the anterior pituitary via binding to the CRF1 receptor, a member of the class B family of G-protein coupled receptors.

[0051] Due to the physiological significance of CRF1, the development of biologically - active small molecules having significant CRF receptor binding activity and which are capable of antagonizing the CRF1 receptor remains a desirable goal and has been the subjectof ongoing research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and substance abuse.

[0052] The pituitary hormone ACTH, under the control of hypothalamic corticotropin - releasing factor (CRF), stimulates uptake of cholesterol and drives the synthesis of pregnenolone initiating steroidogenesis in the adrenal gland. The adrenal cortex is comprised of three zones, which produce distinct classes of hormones many of which are driven by ACTH mobilizing cholesterol through this pathway . Deficiencies in these enzymes as a result of mutation or deletion cause the substrate concentrations to increase. In the most common form of CAH resulting from mutations or deletions in the 21 -hydroxylase gene (CYP21 A2), potent androgens are produced by the adrenal because of the accumulation of the steroid precursors, progesterone and 17-OHP. Plasma levels of 17-OHP can reach 10-1000 times the normal concentration in these cases. These increases result in the overproduction of androgens, specifically androstenedione (A4), testosterone, and dihydroxytestosterone causing virilization in females. In addition, 21 -hydroxylase deficiency in CAH causes insufficient biosynthesis of glucocorticoids and mineralocorticoids, specifically cortisol and aldosterone. Cortisol is a critical negative feedback regulator of hypothalamic CRF secretion and pituitary ACTH release. The lack of glucocorticoid synthesis and release eliminates the restraint on the hypothalamus and pituitary, which causes ACTH levels to increase. The excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting in adrenal hyperplasia.Definitions

[0053] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0054] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range f ormat is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0055] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0056] As used herein, “phosphate buffer” refers to an aqueous solution containing a specific ratio of MM dihydrogen phosphate, MM phosphate-dibasic, MM phosphate-tribasic to reach a specific pH, wherein MM is lithium, sodium, potassium, cesium, magnesium, or calcium, or a combination thereof. The said phosphate buffer can be adjusted with additional acidity regulators such as hydrochloric acid and phosphoric acid to adjust the pH of the solution.

[0057] As defined herein, the term “surfactant” refers to compounds such as poly oxy ethylensorbitan fatty acid eaters (e.g., polysorbates, Tween®), polyoxyethylene alkyl ethers (e.g. Brij®), alkylphenylpolyoxyethylene ethers (e.g. Triton-X®), polyoxyethylenepolyoxypropylene copolymers (e.g. poloxamers, Pluronic®), sodium dodecyl sulfate, or the like. Surfactants are characterized by the ability to form micelles, to preferentially accumulate at liquid-air interfaces, and to disrupt and / or displace protein at liquid -air interfaces. As a result, surfactants generally reduce the surface tension of liquids.

[0058] As used herein, “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (e.g. melting point). Crystalline forms may be anhydrous, or solvate or hydrate forms.

[0059] As used herein, the term “polymer” refers to a chemical compound or mixture of compounds consisting of repeating structural units created through a process of polymerization. As defined herein term “polymer matrix” is defined to mean compositions comprising one or more polymers in which the active agent is dispersed or included with the matrix. The term “solid dispersion” refers to the dispersion of one or more active agents in a polymer matrix at solid state prepared by a variety of methods, including spray drying, the melting (fusion), solvent, or the melting-solvent method. As defined herein, “amorphous solid dispersion” refers to stable solid dispersions comprising an amorphous active agent anda polymer, where “amorphous active agent” means that the amorphous solid dispersion contains active agent in a substantially amorphous solid state form. The term “amorphous” refers to a non-crystalline form of a compound which may be a solid state form of the compound or a solubilized form of the compound. For example, “amorphous” refers to a compound without a regularly repeating arrangement of molecules or external face planes.

[0060] The term “bioavailability” is the degree to which a drug or other substance becomes available to the target tissue or desired biological target after administration.Bioavailability may depend on half life of the drug or other substance or its ability to reach the target.

[0061] As used herein, “ratio” (e.g. 10:90, 20:80, etc.) is defined by either w / v. v / w. v / v. or w / w where w is weight and v is volume.

[0062] As used herein, SPN-001 refers t(tildacerfont).

[0063] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Compounds

[0064] In some embodiments is a compound of Formula I,wherein the compound is prepared from the stable crystalline form, wherein the form of the compound of Formula I is substantially non-crystalline.

[0065] In some embodiments, the crystalline form of Formula I is the starting material. In some embodiments, the crystalline form of Formula I is dissolved in a solvent to form the compound I which is substantially non-crystalline. In some embodiments, the crystallineform of Formula I is dissolved in an organic solvent with a polymer matrix to form the compound of Formula I which is substantially non-crystalline.

[0066] In some embodiments, the organic solvent used to dissolve the crystalline form can be any suitable organic solvent known by one of skill in the art. In some embodiments, the organic solvent is benzene, toluene, benzotrifluoride, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, 1,3 -dioxolane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, trichloromethane, methanol, ethanol, isopropanol, 1 -butanol, tert-butanol, acetone, acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, or dimethyl sulfoxide. In some embodiments, the organic solvent is 1,4- dioxane, 1,3-dioxane, 1,3-dioxolane, tetrahydro furan, dichloromethane, 1,2-dichloroethane, methanol, ethanol, or acetone. In some embodiments, the organic solvent is tetrahydrofuran, dichloromethane, methanol, ethanol, or acetone.

[0067] In some embodiments, the polymer matrix useful for making the compound of Formula I substantially non-crystalline is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof. In some embodiments, the polymer matrix useful for making the compound of Formula I substantially non-crystalline is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit S100, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof. In some embodiments, the polymer matrix useful for making the compound of Formula I substantially non-crystalline is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit LI GO- 55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H. In some embodiments, the polymer matrix useful for making the compound of Formula I substantially non-crystalline is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, or Eudragit LI 00-55.

[0068] In some embodiments, described herein is a composition comprising a noncrystalline form of a compound of Formula I, wherein the composition has improved bioavailability as compared to a composition comprising a crystalline form of a compound of Formula I. In some embodiments, described herein is a composition comprising a noncrystalline form of a compound of Formula I, wherein the composition has improved solubility as compared to a composition comprising a crystalline form of a compound of Formula I.Compositions

[0069] In some embodiments is a composition comprising a polymer matrix and a compound of Formula I,wherein the compound of Formula I is present in a form that is substantially non-crystalline.

[0070] In some embodiments is a composition comprising a polymer matrix and a compound of Formula II:Formula (II) wherein:RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Cnaryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with Ci.C6alkyl;RBis hydrogen, halogen, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Ce alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5 -to 12- membered heterocyclyl, Ce-Ci2aryl, and 5-to 12- membered heteroaryl is optionally substituted with halogen, Ci.C6alkyl, or Ci-Ce alkoxy;R4is hydrogen, halogen, Ci-Cealkyl, -NR4aR4b,-NHC(O)Ci-Cealkyl, -Ci-Cealkylene-O-Ci- Cealkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- memberedheterocyclyl and 5-to 6- membered heteroaryl is optionally substituted with Ci-C6alkyl; andR4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-Cealkyl, -C(O)OCi-Cealkyl, optionally substituted C3- Cecycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C&- Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-Cealkyl; wherein the compound of Formula II is present in a form that is substantially not crystalline.

[0071] RAcan be any suitable functional group described herein. In some embodiments, RAis Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3- C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with one or more Ci-Cealkyl. In some embodiments RAis optionally substituted C3-C12cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally substituted C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with one or more Ci.C6alkyl. In some embodiments, RAis optionally substituted C6-Ci2aryl or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C&- Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with one or more Ci- Cealkyl. In some embodiments, RAis optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted 5- to 12- membered heteroaryl is optionally substituted with one or more Ci-C3alkyl.

[0072] RBcan be any suitable functional group described herein. In some embodiments, RBis hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted 5- to 12- membered heteroaryl is optionally substituted with one or more Ci- C3alkyl substituted C3-Ci2cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6- Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen, Ci-Cealkyl,or Ci-C6alkoxy. In some embodiments, RBis hydrogen, halogen, optionally substituted C3- Cn cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl. In some embodiments, RBis hydrogen, halogen, or optionally substituted Ce-Ci2aryl, wherein the optionally substituted C6-Ci2aryl is optionally substituted with halogen, Ci.C3alkyl, or Ci-C3alkoxy, or a combination thereof. In some embodiments, RBis hydrogen or optionally substituted phenyl, wherein the phenyl is optionally substituted with halogen, methyl, ethyl, propyl, methoxy, ethoxy, or propyloxy.

[0073] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Il-a):Formula (II) wherein:R1and R2are independently ethyl or w-propyl;R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;R4is hydrogen, Br, -NR4aR4b, meth oxy methyl, w-butyl, acetamido, pyridin-4-yl, morpholin-R4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-Cealkyl, Ci-Cealkenyl, and Ci-Cealkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5 - to 12- membered heterocyclyl, C6-Ci2aryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-Cealkyl.

[0074] R1can be any suitable functional group described herein. In some embodiments, R1is Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cealkynyl. In some embodiments, R1is Ci-Cealkyl. Insome embodiments, R1is Ci-C6alkenyl. In some embodiments, R1is Ci-C6alkynyl. In some embodiments, R1is methyl, ethyl, propyl, or butyl. In some embodiments, R1is methyl, ethyl, or propyl. In some embodiments, R1is ethyl, n-propyl, or isopropyl. In some embodiments, R1is ethyl or n-propyl.

[0075] R2can be any suitable functional group described herein. In some embodiments, R2is Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cealkynyl. In some embodiments, R2is Ci-Cealkyl. In some embodiments, R2is Ci-Cealkenyl. In some embodiments, R2is Ci-Cealkynyl. In some embodiments, R2is methyl, ethyl, propyl, or butyl. In some embodiments, R2is methyl, ethyl, or propyl. In some embodiments, R2is ethyl, n-propyl, or isopropyl. In some embodiments, R2is ethyl or n-propyl.

[0076] R3can be any suitable functional group described herein. In some embodiments, R3is hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6haloalkyl, or Ci- Cealkoxy. In some embodiments, R3is hydrogen, halogen, Ci-Cealkyl, Ci-Ce haloalkyl, or Ci-C6alkoxy. In some embodiments, R3is hydrogen, F, Cl, Br, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, or propyloxy. In some embodiments, R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy. In some embodiments, R3is hydrogen, F, Cl, Br, methyl, or trifluoromethyl. In some embodiments, R3is Cl or Br.

[0077] R4can be any suitable functional group described herein. In some embodiments, R4is hydrogen, halogen, Ci-C6alkyl, -NR4aR4b,-NHC(O)Ci-C6alkyl, -Ci-C6alkylene-O-Ci- C6alkyl, optionally substituted 5 - to 6- membered heterocyclyl, or optionally substituted 5 - to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5- to 6- membered heteroaryl is optionally substituted with Ci-Ce alkyl. In some embodiments, R4is hydrogen halogen, Ci-Cealkyl, -NR4aR4b, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl. In some embodiments, R4is -NR4aR4b, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl. In some embodiments, R4is -NR4aR4b. In some embodiments, R4is optionally substituted 5- to 6- membered heterocyclyl. In some embodiments, R4is optionally substituted 5- to 6- membered heteroaryl. In some embodiments, R4is -NRaRb, pyridinyl, morpholinyl, ortetrazolyl optionally substituted withmethyl. In some embodiments, R4is -NRaRb, pyridin-4-yl, morpholin-4-yl, orIn some embodiments, R4is morpholin-

[0078] R4acan be any suitable functional group described herein. In some embodiments, R4ais hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci- C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci- Cealkyl, -C(O)OCi-Cealkyl, optionally substituted C3-Cecycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-Cealkyl. In some embodiments, R4ais hydrogen, optionally substituted Ci-Cealkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci- C6alkynyl. In some embodiments, R4ais hydrogen or optionally substituted Ci-C6alkyl. In some embodiments, R4ais Ci-C3alkyl. In some embodiments, R4ais hydrogen.

[0079] R4bcan be any suitable functional group described herein. In some embodiments, R4bis hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci- Cealkenyl, and Ci-Cealkynyl is optionally substituted with one or more amine, -C(O)Ci- C6alkyl, -C(O)OCi-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-Cecycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl. In some embodiments, R4bis hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci- Cealkynyl. In some embodiments, R4bis hydrogen or optionally substituted Ci-Cealkyl. In some embodiments, R4bis Ci-C3alkyl. In some embodiments, R4bis hydrogen.

[0080] In some embodiments, R4is -NRaRb, and Raand Rbare independently Ci-C3alkyl.

[0081] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the polymer matrix is polyvinylpyrrolidione, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit SI 00, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, EudragitL100-55, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M.

[0085] In some embodiments, the composition comprising a polymer matrix and a compound of Formula I further comprises a surfactant. Surfactants can be derived from polyethylene glycol (PEG) polymers, sodium alkyl ether sulfates, and poloxamers. In some embodiments, the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof. In some embodiments, the surfactant is Kolliphor RH40, TPGS, or a combination thereof. In some embodiments, the surfactant is TPGS.

[0086] In some embodiments, the polymer matrix is HPMCAS M and the surfactant is TPGS.

[0087] In some embodiments the ratio of the compound of Formula I and polymer matrix is about 10:90 to about 70:20. In some embodiments the ratio of the compound of Formula I and polymer matrix is about 10:90 to about 50:50. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to about 40:60. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to about 30:70. In some embodiments, the composition comprising a polymer matrix and a compound of Formula I further comprises a surfactant. In some embodiments, the ratio of the compound of Formula I, polymer matrix, and surfactant is in a ratio of about 25 :60: 10.

[0088] In some embodiments, the composition has a bioavailability of greater than 50%. In some embodiments, the composition has a bioavailability of greater than 60%. In some embodiments, the composition has a bioavailability of greater than 75%. In some embodiments, the composition has a bioavailability of greater than 85%. In some embodiments, the composition has a bioavailability of greater than 90%. In some embodiments, the composition has a bioavailability of greater than 95%.Methods of Making Amorphous Solid Dispersions

[0089] In some embodiments, the present disclosure provides a method of making an amorphous solid dispersion (ASD), wherein the amorphous solid dispersion comprises a polymer matrix and a compound of Formula I,wherein the method comprises mixing a compound of Formula I with a polymer matrix in a buffer solution.

[0090] In some embodiments, the compound of Formula I is substantially non-crystalline. In some embodiments, the buffer solution is a phosphate buffer. In some embodiments, the phosphate buffer is 10 mM phosphate buffer to 100 mM phosphate buffer. In some embodiments, the phosphate buffer comprises Tween. In some embodiments, the phosphate buffer comprises 0.1 to 10% Tween 80. In some embodiments, the phosphate buffer comprises 0.1% to 5% Tween 80. In some embodiments, the phosphate buffer comprises 0.1% to 1% Tween 80. In some embodiments, the phosphate buffer is 50 mM phosphate buffer pH 6.8 with 1.0% Tween 80.

[0091] In some embodiments, the compound of Formula I and the polymer matrix is first dissolved in an organic solvent. In some embodiments, the organic solvent is benzene, toluene, benzotrifluoride, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert -butyl ether, 1,4-dioxane, 1,3 -dioxane, 1,3 -dioxolane, tetrahydrofuran, dichloromethane, 1,2- dichloroethane, trichloromethane, methanol, ethanol, isopropanol, 1 -butanol, tert-butanol, acetone, acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, or dimethyl sulfoxide. In some embodiments, the organic solvent is 1,4-dioxane, 1,3-dioxane, 1,3- dioxolane, tetrahydrofuran, dichloromethane, 1,2 -dichloroethane, methanol, ethanol, or acetone. In some embodiments, the organic solvent is tetrahydrofuran, dichloromethane, ethanol, or acetone. In some embodiments, the organic solvent is removed, and the buffer solution is added.

[0092] In some embodiments, the polymer matrix is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit SI 00, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55,PVOH or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00, Eudragit LI 00-55, or a combination thereof. In some embodiments, the polymer matrix is HPMCAS M.

[0093] In some embodiments, the ASD comprises a polymer matrix and a compound of Formula I further comprises a surfactant. In some embodiments, the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof. In some embodiments, wherein the surfactant is Kolliphor RH40, TPGS, or a combination thereof. In some embodiments, the surfactant is TPGS. In some embodiments, the polymer matrix is HPMCAS M and the surfactant is TPGS.

[0094] In some embodiments the ratio of the compound of Formula I and polymer matrix is about 10:90 to about70:20. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 10:90 to about 50:50. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to about 40:60. In some embodiments, the ratio of the compound of Formula I and polymer matrix is about 20:80 to about 30:70. In some embodiments, the ratio of the compound of Formula I, polymer matrix, and surfactant is in a ratio of about 25:65:10.

[0095] In some embodiments, the composition has a bioavailability of greater than 50%. In some embodiments, the composition has a bioavailability of greater than 60%. In some embodiments, the composition has a bioavailability of greater than 75%. In some embodiments, the composition has a bioavailability of greater than 85%. In some embodiments, the composition has a bioavailability of greater than 90%. In some embodiments, the composition has a bioavailability of greater than 95%.Methods of Treatment

[0096] In one embodiment, provided herein are methods for treating or preventing a tumor, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for treating or preventing a benign tumor, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for treating or preventing a malignant tumor,comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or pro drug thereof. In one embodiment, provided herein are methods for treating or preventing an adrenal tumor, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for treating or preventing an adrenal rest tumor, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0097] In one embodiment, provided herein are methods for treating or preventing infertility, comprising administering a composition comprising a compound of Formula (I) or Formula (II); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for treating or preventing male infertility, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for improving or increasing sperm count, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for improving or increasing sperm motility, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for improving or increasing sperm morphology, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, provided herein are methods for treating or preventing female infertility, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0098] In one embodiment, provided herein are methods for treating or preventing a proliferative or hyperproliferative disease or disorder, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is a cancer of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system.

[0099] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin’s disease and non-Hodgkin’s disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom’s macroglobulinernia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, aligodendrogliorna, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget’s disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing’s disease, prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamouscell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and / or uterer); (40) Wilms’ tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, and papillary adenocarcinomas See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

[0100] In some embodiments is a method of treating congenital adrenal hyperplasia (CAH), the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0101] Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH affects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: 1) glucocorticoids, which gauge the body's response to stress, illness, or injury; 2) mineralocorticoids, which regulate salt and water levels; and 3) androgens, which are male sex hormones. An enzyme deficiency may make the body unable to produce one or more of these hormones, which in turn may result in the overproduction of another type of hormone precursor in order to compensate for the loss.

[0102] Disclosed herein are methods of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering a composition described herein. In some embodiments, the methods described herein result in the reduction of a level of a hormone. Such hormones include deoxycorticosterone, 11 -deoxy cortisol, cortisol, corticosterone, aldosterone, pregnenolone, 17a-hydroxy pregnenolone, progesterone, 17-OHP, dehydroepiandrosterone, androstenediol, A4, testosterone, dihydrotestosterone, estrone, estradiol, estriol, and ACTH. In some embodiments, the methods described herein result in the reduction of 17-OHP levels. In some embodiments, the methods described herein result in the reduction of A4 levels. In some embodiments, the methods described herein result in the reduction of ACTH levels, also known as corticotropin.

[0103] In some embodiments, is a method of treating testicular adrenal rest tumors (TART) or ovarian adrenal rest tumors (OART), the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0104] Testicular adrenal rest tumors (TART) and ovarian adrenal rest tumors (OART) are ACTH-responsive lesions of the testes and ovaries derived from adrenal tissue interchelated within these organs during embryogenesis. In response to high ACTH, hyperplasia of this tissue occurs, resulting in single or multiple lesions that may cause painand infertility. The identification of compounds that modulate CRF function and downstream processes is an ongoing challenge.

[0105] In one embodiment, provided herein are methods for treating or preventing testicular adrenal rest tumors (TART) in a subject, comprising administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the subject has congenital adrenal hyperplasia (CAH).

[0106] In one embodiment, provided herein are methods for treating or preventing ovarian adrenal rest tumors (OART) in a subject, comprising administering composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the subject has congenital adrenal hyperplasia (CAH).

[0107] In an aspect provided herein, is a method of treating or preventing testicular adrenal rest tumors (TART), comprising administering to a subject in need thereof a composition comprising a corticotropin-releasing factor type-1 (CRFi) antagonist or a pharmaceutically acceptable salt thereof.

[0108] In an aspect provided herein, is a method of treating or preventing ovarian adrenal rest tumors (OART), comprising administering to a subject in need thereof a composition comprising a corticotropin-releasing factor type-1 (CRFi) antagonist or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments is a method of treating method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0110] Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting an estimated 12% of reproductive aged women. Women with PCOS may have polycystic ovarian morphologic features, ovulatory dysfunction in the form of infrequent or prolonged menstrual periods, and hyperandrogenism in the form of excess male hormone levels. This complex disorder has both environmental influences, such as obesity and insulin resistance, and inappropriate endocrine signaling from the hypothalamus and pituitary glands as contributors. Hyperandrogenism presents clinically as hirsutism and acne and biochemically with elevated serum androgen levels. Androgen and androgen precursors can be produced and secreted by the ovaries and also by the adrenal cortices in about the same amount in response to stimulation by pituitary derived luteinizing hormone (LH) to the ovaries and adrenocorticotropic hormone (ACTH) to the adrenal gland, respectively.Emerging data indicate that PCOS patients can be categorized according to whether the source of excessive androgen is primarily from the ovaries, namely, functional ovarian hyperandrogenism (FOH), or the adrenal glands, namely, functional adrenal hyperandrogenism (FAH), both (FOH and FAH), or neither and attributable to either insulin resistance / obesity or of unknown origin. A majority or about two -thirds of cases have functionally typical PCOS (PCOS-T) that is due to typical FOH, characterized by hyperresponsiveness of 17 -hydroxyprogesterone (17-OHP). About one fifth of cases have functionally atypical FOH (PCOS-A), lacking 17-OHP hyperresponsiveness. Within these two FOH populations, about one-third may have both FOH and FAH. About 8% of PCOS cases are attributed to either obesity and the remainder are unknown or idiopathic in nature. Only about 3-5% PCOS cases are due to isolated FAH with androgen responsiveness to ACTH.

[0111] Disclosed herein are methods of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a composition described herein. In some embodiments, the subject in need thereof has PCOS-FAH. In some embodiments, the subject in need thereof has PCOS-FOH+FAH. In some embodiments, the methods described herein result in the reduction of a level of a hormone. Such hormones include deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, pregnenolone, 17a-hydroxy pregnenolone, progesterone, 17-OHP, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenediol, androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), estrone, estradiol, estriol, 1 ip-hydroxyandrostenedione (110HA4), 11|3- hydroxytestosterone (11OHT), 11 -ketoandrostenedione (11KA4), 11 -ketotestosterone (11KT), 1 ip-hydroxy-5a-androstenedione (110HDHA4), 1 l-keto-5a-androstenedione (11KDHA4), 1 ip-hydroxy dihydrotestosterone (11OHDHT), 11 -ketodihydrotestosterone (11KDHT) and ACTH. In some embodiments, the methods described herein result in the reduction of 17-OHP levels. In some embodiments, the methods described herein result in the reduction of A4 levels. In some embodiments, the methods described herein result in the reduction of ACTH levels. In some embodiments, the methods described herein result in the reduction of DHEA levels. In some embodiments, the methods described herein result in the reduction of DHEAS levels. In some embodiments, the methods described herein result in the reduction of testosterone (T) levels. In some embodiments, the methods described herein result in the reduction of DHT levels. In some embodiments, the methods described herein result in the reduction of 110HA4 levels. In some embodiments, the methods described herein result in the reduction of 11OHT levels. In some embodiments, the methods describedherein result in the reduction of 11KA4 levels. In some embodiments, the methods described herein result in the reduction of 11KT levels.

[0112] In some embodiments is a method of treating a neurological disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0113] Neurological diseases and disorders include, but are not limited to, epilepsy, learning disabilities, neuromuscular disorders, atism, brain tumors, cerebral palsy, attention deficit disorder (ADD) / attention-deficit / hyperactivity disorder (ADHD), depression, Alzheimer’s Disease, Parkinson’s Disease, Asperger Syndrome, cerebral aneurysm, head injury, migraine, stroke, dementia, diabetic neuropathy, Huntington’s Disease, and muscular dystrophy.

[0114] In some embodiments, the neurological disease or disorder is depression, epilepsy, migraine, stroke, or dementia. In some embodiments, the neurological disease or disorder is depression.EXAMPLES

[0115] The following illustrative examples are representative of embodiments of the stimulation, systems, and methods described herein and are not meant to be limiting in any wayExample 1. Solubility of Crystalline SPN-001 (Formula I)

[0116] Pure crystalline SPN-001 was characterized in order to provide a reference for amorphous composition study. Multiple physical measurements were taken of a sample of pure crystalline SPN-001. A differential scanning calorimetry (DSC) measurement was taken of the pure crystalline SPN-001 and is shown in FIG. 1. Further, an X-ray powder diffraction (XRPD) was taken of the pure crystalline SPN-001 and is shown in FIG. 2.Table 1: Summary of solubility tests of the standard crystalline SPN-001 across multiple solvents and excipientsSolubility was measured after mixing with room temperature.Example 2. In silica modeling of SPN-001 with polymers

[0117] In order to rapidly develop promising amorphous solid dispersions formulations, molecular modelling was performed to identify polymers and substrates compatible with SPN-001. In silico modelling was performed based on Hansen solubility parameters within the HSPiP program algorithm. The modelling proceeded by first defragmenting the SPN-001 structure according to HSPiP algorithms and deriving solubility parameters based on Hansen solubility parameters. Thereafter, miscible pairs were identified with relevant excipients based on the SPN-001 solubility parameters. The maximum miscibility limits based on Gibbs Free Energy calculations was then estimated for SPN-001 and many polymer matrices.

[0118] Polymer matrices calculated to have a smaller difference in Hansen solubility parameter values with SPN-001 were prioritized for experimental formulation development. This concept is emulated mathematically as A<5t=<5tSPN-001-<5tPoZymer<7.0MPa0.5. Based on the HSP calculations, HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit LI 00 and Eudragit LI 00 -55 polymers showthe least solubility parameter differences (most likely to be compatible with API) as shown in FIG. 3. Several delta values are shown in Table 2. This data was used for rationally based testing of experimental formulations of SPN-001.Table 2. Calculated Hanson Solubility parameters between SPN-001 and polymer matrix compositionsExample 3. Screening of SPN-001 Formulations

[0119] To assess the concentrations of SPN-001 in ASD formulations, a UV absorbance curve was analyzedfor SPN-001 in methanol. The lambda max frequency was determined, and thereafter a concentration curve was verified with experimentally known concentrations of SPN-001 in methanol.

[0120] Thereafter, a screening was performed to determine the polymer matrix formulations with solubility of SPN-001 in an ASD formulation. Two sets of screenings were performed, with the first one testing polymer matrices and the second screening testing surfactants as well.Microevaporation screening

[0121] Measurement of re-dissolution behavior of SPN-001 and test polymer matrix compositions was used to verify the behavior and suitability of the polymer system (ASD). Experimental screening ofpolymer matrices identified as promising from in silico modelling underwent the following procedure; SPN-001 and test polymer were dissolved individually in an organic solvent and mixed in centrifuge tubes. Organic solvent was removed via vacuum concentrator. The dry solid was then solvated in pH 6.8 phosphate buffer and mixed. The UV spectra of the resulting solutions was recorded at 4, 10, and 30 minutes after mixing. The polymer matrices screened include: 30:70 SPN-001 :HPMCAS M, 25:75 SPN-001 :HPMCAS L 20:80 SPN-001 :KollidonVA64, 20:80 SPN-001 :EudragitLl 00, and 20:80 SPN-001 :EudragitLl 00-55. The HPMCAS-M polymer matrix shows the highest redissolution of SPN-001 under the experimental conditions (FIG. 4).Micro-evaporation screening with surfactants (Set 2)

[0122] The ASD formulation was further tested with surfactants to increase suitability for biodistribution. Addition of surfactants / solubilizers (10%) to the polymer matrix was tested for possible enhancement of spring-parachute effect (supersaturation). The polymer and surfactant compositions tested include: SPN-001+ HPMCAS M + PEG1500 (25:65:10), SPN-001+ HPMCAS M + SLS (25:65:10), SPN-001+ HPMCAS M + Kolliphor RH40 (25:65:10), SPN-001+ HPMCAS M + TPGS (25:65:10), and SPN-001+ HPMCAS M + Poloxamer 407 (25:65:10).

[0123] Best results for highest dissolution behavior were the SPN-001 : HPMCAS M : TPGS (25:65:10) yielding a SPN-001 concentration of 95pg / mL (FIG. 5). 48 times higher dissolution than SPN-001 alone. Addition of the surfactant TPGS to HPMCAS M matrix improved dissolution even further compared to HPMCAS M matrix without surfactant / solubilizer.Example 4. X-ray powder diffraction of SPN-001 formulations

[0124] To determine the amorphous property of SPN-001 polymer formulations, X-ray powder diffraction was performed on the SPN-001 : HPMCAS (30:70) and SPN-001 : HPMCAS M:TPGS (25:65:10). SPN-001, polymer and surfactants were dissolved individually in an organic solvent and mixed in centrifuge tubes. Solvent was removed using a vacuum concentrator. SPN-001 formulations show the API (SPN-001) is retained in an amorphous state; no crystalline peaks were observed (FIG. 6 and FIG. 7).Example 5. Pharmacokinetic study of SPN-001 formulations in Sprague-Dawley rats

[0125] This study was conducted to evaluate and compare pharmacokinetic properties of SPN-001 in male Sprague-Dawley rats following intravenous administration at 1 mg / kg and oral administration at 50 mg / kg in three different formulations versus SPN-001 without polymer. The items were prepared with the amounts described in Table 3.Table 3. Rat pharmacokinetic studies

[0126] The concentrations of SPN-001 in rat plasma samples were determined by LC- MS / MS with the dynamic ranges of 1 - 2000 ng / mL and 10 - 10000 ng / mL. Pharmacokinetics including plasma exposure of SPN-001 were evaluated. Comparisons of the major plasma PK parameters of SPN-001 are summarized in Table 4.

[0127] Formulations of SPN-001 were preparedin DMSO / PEG400 / Water (10:70:20) for IV administration and 50 mM Phosphate buffer pH 6.8 with 1.0 % Tween 80 for PO administrations in the morning of the dosing day. The dose volumes were 1 mL / kg for IV dose and 10 mL / kg for PO dose. Formulation preparation details are summarized in Table 3 and Table 4.Table 4. Dosing information of ASD formulation test groups. Bioavailability (F) was based on calculation of the individual AUCinf of PO divided by the average AUCinf of IV corrected by dose.

[0128] A total of 8 male Sprague-Dawley rats were randomly divided into 4 groups (2 rats per group). 2 animals (Group 1) were dosed with SPN-001 by IV administration at 1 mg / kg with a dosing volume of 1 mL / kg and the other 6 animals (Groups 2, 3 and 4) weredosed with SPN-001, ASD1, and ASD2 by per os (PO) administration at 50 mg / kg with a dosing volume of 10 mL / kg, respectively. The animals underwent jugular vein cannulation (JVC) surgery in a laminar flow cabinet in the BioDuro animal facility and recovered 3 ~ 4 days prior to dosing. Blood (~ 0.25 mL per time point) was collected via jugular vein into EDTA-K2tubes, at the following time-points: 0.0833 (IV only), 0.25, 0.5, 1, 2, 4, 8 and24 hr post-dose. Immediately following blood collection, the samples were inverted several times and put on wet ice pending centrifugation. Within 30 minutes of collection, plasma was separated by centrifugation at 6000 rpm for 5 minutes at 4 °C. All plasma samples were stored at -20 °C before the study endpoint and transferred to -80 °C after the last sample collection. The plasma concentration and times were recorded in FIG. 8.

[0129] For each analytical batch of plasma samples, standard and quality control (QC) samples were freshly prepared in blank Sprague -Dawley rat plasma (K2EDTA anticoagulant). The standard curves ranges used for first plasma analysis were 1 - 2000 ng / mL, three concentration levels of QC samples in rat plasma were used at 2, 500 and 1600 ng / mL. A 5x dilution QC sample (in triplicate) was used at 8000 ng / mL. The standard curves used for plasma reanalysis ranges were 10 - 10000 ng / mL, three concentration levels of QC samples in rat plasma were used at 20, 1600, and 8000 ng / mL. For a batch with a sample number in the range of 10 ~ 100, two sets of standard curves and QCs were included. If a batch contained more than 100 samples, two sets of standard curves and three sets of QCs were included; if the total number of samples was < 10, only one set of standard curves and two sets of QCs were included.

[0130] Plasma samples in each group at the same timepoint were pooled for bioanalysis. To an aliquot 50 pL of each standard, QC, dilution QC, control blank and study sample, 200 pL of internal standard (5 ng / mL Terfenadine) in methanol / acetonitrile (1 :1, v / v) was added. For double blank, 200 pL of blank methanol / acetonitrile (1 :1, v / v) was added to the blank plasma. The samples were mixed for 1 minute and centrifuged at 4000 rpm at 4 °C for 15 minutes; supernatants were transferred and diluted (5 x dilution) in methanol / water (1 :1, v / v, with 0.1% FA).Dose Concentration Verification

[0131] The dose solution was firstly prepared in blank male rat plasma in triplicate for dose verification. The dose solution was prepared by first pipetting 50 pL of each dose formulation into a 20 mL glass bottle and adding 10 mL MeOH for concentration verification (200x dilution). Next, pipetting 100 pL of each PO dose solution from step 1 into 900 pL MeOH (1 Ox dilution). Lastly, 5 pL of each diluted dose solution (2000 x diluted for IV dose,20000 x diluted for PO dose) from step 1 or step 2 was added into 50 pL of blank male rat plasma, respectively. Then 200 pL of methanol / acetonitrile (1 : 1, v / v) containing internal standard (5 ng / ml of Terfenadine) was added for LC-MS / MS analysis. This step was processed exactly as the standards. The results are summarized in Table 5.Table 5. SPN-001 Rat dose verification test data. Percent relative error (RE) is the difference between the mean concentration (n=3) minus the nominal concentration divided by the nominal concentration * 100. Percent coefficient of variance (CV) is the standard deviation of concentration (n=3) divided by the average concentration.

[0132] The dose solution for dose reanalysis was prepared in neat solvents in triplicate for dose verification: The dose solution was prepared by: pipetting 5 pL of SPN-001 PO and ASD1 dose formulation into 995 pL MeOH, respectively (200x dilution), pipetting 200 pL of each dose solution from step 1 into 800 pL MeOH, respectively (5x dilution), pipetting 100 pL of each dose solution from step 2 into 900 pL MeOH, respectively (lOx dilution).

[0133] Additionally, 50 pL of each diluted dose solution (10000 x diluted for API and ASD1 PO dose) from step 3 was added into 200 pL of methanol / acetonitrile (1 : 1, v / v) containing internal standard (5 ng / ml of terfenadine) and then diluted (5x dilution) in methanol / water (1 :1, v / v, with 0.1%FA) for LC-MS / MS analysis. The dose verification results are summarized in Table 5. Separate HPLC analysis were conducted using ACE Excel 5 C4 2.1 x 50 mm Column, Kinetex 2.6p C18 100A column (50 mm * 3.00 mm) and ACQUITY UPLC BEH Cl 8 1.7 pm column (50 mm * 2.1 mm) to determine the concentrations of SPN-001.

[0134] All the mass spectrometer (API 6500+) used for plasma analysis, mass spectrometer (API 4000) used for plasma Reanalysis and mass spectrometer (API 5500) usedfor dose verification were operated in positive ion multiple reaction monitoring mode (MRM). The MRM channels of SPN-001 and the internal standard (Terfenadine) were 420.22 / 385.30 and 472.40 / 436.40, respectively.

[0135] Data collection used for plasma analysis was performed using Analyst Software version 1.7.1 including linear regression with weighting (l / x2) performed using the same software. The retention times of SPN-001 and Terfenadine were 1.66 min and 1.54 min, respectively. Representative LC-MS / MS chromatograms are shown in Appendix V. And data collection used for plasma reanalysis was performed using Analyst Software version 1.6.3 including linear regression with weighting (1 / X2) performed using the same software. The retention times of SPN-001 and terfenadine were 2.15 min. Data collection used for dose verification was performed using Analyst Software version 1 .7.2 including linear regression with weighting (l / x2) performed using the same software. The retention times of SPN-001 and Terfenadine were 1.87 min and 1.57 min, respectively.

[0136] The measured plasma concentrations at each time -point, the nominal sample collection time, and intended dosages were used for pharmacokinetic analysis. The PK parameters of SPN-001 were determined by non-compartmental analysis using WinNonlin Version 8.0 (Pharsight). The major pharmacokinetic parameters are reported, including Cmax(the maximum plasma concentrations), AUCiast (the area under the plasma concentration time curve up to the time of the last quantifiable concentration), AUCinf (the value of AUC extrapolated to infinity), MRT (the mean residence time), Tmax(the time of maximum plasma concentrations), TI / 2(half-life) and F% (bioavailability).

[0137] There were no clinical signs observed in male Sprague -Dawley rats following intravenous administration at 1 mg / kg and oral administration in three different formulations at 50 mg / kg. The plasma concentrations for each animal are listed in Table 6. SPN-001 was measurable in the plasma samples collected from all dosing groups for up to 24 hr post-dose (last sampling time). The plasma concentration -time profiles of SPN-001 following intravenous and oral administrations to male Sprague -Dawley rats are presented in FIG. 8. Table 6. Mean plasma concentrations of SPN-001 in male Sprague-Dawley rats following intravenous at 1 mg / kg and oral administration at 50 mg / kg to male Sprague-Dawley rats.

[0138] Following single intravenous administration of SPN-001 at 1 mg / kg, SPN-001 was cleared from plasma with a half-life (Tl / 2) of 5.01 hours with volume distribution at steady state (Vss) of 1.97 L / kg and the clearance is 0.618 L / hr / kg. Following single oral administration of SPN-001 at 50 mg / kg in three different formulation forms, the values of Cmax comparison were 6680 ng / mL (ASD2) > 4390 ng / mL (ASD1) > 1180 ng / mL (SPN- 001) and the values of AUClast were 94908 hr*ng / mL (ASD2) > 66276 hr*ng / mL (ASD1) > 18269 hr*ng / mL (SPN-001).

[0139] Following single oral administration in Sprague-Dawley rats of SPN-001 at 50 mg / kg, the values of bioavailability of SPN-001 in three formulation forms comparison are SPN-001 ASD2 (SPN-001 : HPMCAS- M 30:70) (134%) > SPN-001 ASD1 (SPN-001 : HPMCAS-M: TPGS 25:65:10) (99.0%) > SPN-001 API (24.6%). Pharmacokinetics analysis indicated that two amorphous solid dispersion formulations could increase the bioavailability of SPN-001 from 24.6% to more than 90.0%, and the ASD formulation of SPN-001 : HPMCAS-M 30:70 has a better bioavailability than the other ASD formulation of SPN-001 : HPMCAS-M: TPGS 25:65:10. The pharmacokinetic results are summarized in Table 7 below.Table 7. Pharmacokinetic parameters of SPN-001 following IV at 1 mg / kg and oral administrations at 50 mg / kg to male Sprague -Dawley rats. Bioavailability (F) was based on calculation of the individual AUCinf of PO divided by the average AUCinf of IV corrected by dose.Example 6. Pharmacokinetic study of SPN-001 formulations in Beagle dogs

[0140] This study was conducted to evaluate and compare pharmacokinetic properties of SPN-001 in male Beagle dogs following intravenous administration at 2 mg / kg and oral administration at 20 mg / kg in three different formulations versus SPN-001 without polymer. The powders were filled into capsules for oral administration as described in Table 8.Table 8. Dog pharmacokinetic studies

[0141] The concentrations of SPN-001 in dog plasma samples were determined by LC- MS / MS with the dynamic ranges of 0.2 - 200 ng / mL and 10 - 1600 ng / mL. Pharmacokinetics including plasma exposure of SPN-001 were evaluated. Comparisons of the major plasma PK parameters of SPN-001 are summarized in Table 9.

[0142] Formulations of SPN-001 were preparedin DMSO / PEG400 / Water (10:70:20) for IV administration with a dose volume of 1 mL / kg for IV administration. Spray dry dispersions and crystalline SPN-001 powders were filled into a capsule for PO administration. Formulation preparation details are summarized in Table 8 and Table 9. Table 9. Dosing information of ASD formulation test groups. Bioavailability (F) was based on calculation of the individual AUCinf of PO divided by the average AUCinf of IV corrected by dose.

[0143] A total of 16 male Beagle dogs were randomly divided into 4 groups (4 dogs per group). Four animals (Group 1) were dosed with SPN-001 by IV administration at 2 mg / kg with a dosing volume of 1 mL / kg and the other 12 animals (Groups 2, 3 and 4) were dosed with SPN-001, ASD1, and ASD2 by per os (PO) administration at 20 mg / kg. The animals underwent jugular vein cannulation (JVC) surgery in the BioDuro animal facility and recovered 3 ~ 4 days prior to dosing. Blood (~ 0.8 mL per time point) was collected via jugular vein into EDTA-K2tubes, at the following time-points: 0.0833 (IV only), 0.25 (IV only), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hr post-dose. Immediately following blood collection, the samples were inverted several times and put on wet ice pending centrifugation. Within 30 minutes of collection, plasma was separated by centrifugation at 3000 rpm for 10 minutes at 4 °C. All plasma samples were stored at -20 °C before the study endpoint and transferred to -80 °C after the last sample collection. The plasma concentration and times were recorded in FIG. 9.

[0144] For each analytical batch of plasma samples, standard and quality control (QC) samples were freshly prepared in blank Beagle dog plasma (K2EDTA anticoagulant). The standard curves ranges used for plasma analysis were 0.2 - 200 ng / mL, four concentration levels of QC samples in dog plasma were used at 0.2, 1.0, 50.0 and 160 ng / mL. A lOx dilution QC sample (in triplicate) was used at 1600 ng / mL. The standard curves used forplasma reanalysis ranges were 0.2 - 200 ng / mL, four concentration levels of QC samples in dog plasma were used at 0.2, 1.0, 50.0 and 160 ng / mL.

[0145] To an aliquot 50 pL of each standard, QC, dilution QC, control blank and study sample, 200 pL of internal standard (100 ng / mL Gilbenclamide) in methanol / acetonitrile (1 :1, v / v) was added. For double blank, 200 pL of blank methanol / acetonitrile (1 : 1, v / v) was added to the blank plasma. The samples were mixed for 1 minute and centrifuged at 4000 rpm at 4 °C for 15 minutes; supernatants were transferred and diluted (10x dilution) in methanol / water (1 :1, v / v, with 0.1% FA) for injection.Dose Concentration Verification

[0146] The dose solution was firstly prepared in blank male dog plasma in triplicate for dose verification. The dose solution was prepared by first pipetting 50 pL of each dose formulation into a 20 mL glass bottle and adding 10 mL MeOH for concentration verification (200x dilution). This step was processed exactly as the standards. The results are summarized in Table 10.Table 10. SPN-001 Dog dose (IV) verification test data. Percent relative error (RE) is the difference between the mean concentration (n=3) minus the nominal concentration divided by the nominal concentration * 100. Percent coefficient of variance (CV) is the standard deviation of concentration (n=3) divided by the average concentration.

[0147] The measured plasma concentrations at each time -point, the nominal sample collection time, and intended dosages were used for pharmacokinetic analysis. The PK parameters of SPN-001 were determined by non-compartmental analysis using WinNonlin Version 8.0 (Pharsight). The major pharmacokinetic parameters are reported, including Cmax(the maximum plasma concentrations), AUCiast (the area under the plasma concentration time curve up to the time of the last quantifiable concentration), AUCinf (the value of AUC extrapolated to infinity), MRT (the mean residence time), Tmax(the time of maximum plasma concentrations), TI / 2(half-life) and F% (bioavailability).

[0148] There were no clinical signs observed in male Beagle dogs following intravenous administration at 2 mg / kg and oral administration in three different formulations at 20 mg / kg. The plasma concentrations for each animal are listed in Table 11. SPN-001 was measurablein the plasma samples collected from all dosing groups for up to 48 hr post-dose (last sampling time). The plasma concentration -time profiles of SPN-001 following intravenous and oral administrations to male Beagle dogs are presented in Table 11.Table 11. Mean plasma concentrations of SPN-001 in male Beagle dogs following intravenous at 2 mg / kg and oral administration at 20 mg / kg to male Beagle dogs.

[0149] Following single intravenous administration of SPN-001 at 2 mg / kg, SPN-001 was cleared from plasma with a half-life (Tl / 2) of 17 hours with a volume distribution at steady state (Vss) of 18.9 L / kg and the clearance is 23.1 L / hr / kg. Following single oral administration of SPN-001 at 20 mg / kg in three different formulation forms, the mean values of Cmax comparison were 737 ng / mL (ASD1) > 602 ng / mL (ASD2) > 434 ng / mL (SPN- 001) and the values of AUClast were 5945 hr*ng / mL (ASD1) > 4682 hr*ng / mL (ASD2) > 3886 hr*ng / mL (SPN-001).

[0150] Following single oral administration in male Beagle dogs of SPN-001 at 20 mg / kg, the values of bioavailability of SPN-001 in three formulation forms comparison are SPN-001 ASD1 (SPN-001 : HPMCAS- M 30:70) 44.2% > SPN-001 ASD2 (SPN-001 : HPMCAS-M: TPGS 22:68:10) 32.5% > SPN-001 API 27.4%. Pharmacokinetics analysis indicated that two amorphous solid dispersion formulations could increase the bioavailability of SPN-001 from 27.4% to more than 44.2%, and the ASD formulation of SPN-001 : HPMCAS-M 30:70 has a better bioavailability than the other ASD formulation of SPN-001 : HPMCAS-M: TPGS 22:68:10. The pharmacokinetic results are summarized in Table 12 below.Table 12. Pharmacokinetic parameters of SPN-001 following IV at 2 mg / kg and oral administrations at 20 mg / kg to male Beagle dogs. Bioavailability (F) was based on calculation of the individual AUCinf of PO divided by the average AUCinf of IV corrected by dose.

[0151] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising a polymer matrix and a compound of Formula I:wherein the compound of Formula I is present in a form that is substantially noncrystalline.

2. The composition of claim 1, wherein the polymer matrix is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof.

3. The composition of claim 1 or 2, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit S100, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC E15, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof.

4. The composition of claim 3, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof.

5. The composition of claim 4, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, or a combination thereof.

6. The composition of claim 5, wherein the polymer matrix is HPMCAS M.

7. The composition of any one of claims 1 to 6, wherein the composition further comprises a surfactant.

8. The composition of claim 7, wherein the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof.

9. The composition of claim 8, wherein the surfactant is Kolliphor RH40, TPGS, or a combination thereof.

10. The composition of claim 9, wherein the surfactant is TPGS.

11. The composition of any one of claims 7 to 10, wherein the polymer matrix is HPMCAS M and the surfactant is TPGS.

12. The composition of any one of claims 1 to 11, wherein the ratio of the compound of Formula I and polymer matrix is about 10:90 to 50:50.

13. The composition of claim 12, wherein the ratio of the compound of Formula I and polymer matrix is about 20:80 to 40:60.

14. The composition of claim 13, wherein the ratio of the compound of Formula I and polymer matrix is about 20:80 to 30:70.

15. The composition of any one of claims 12 to 14, further comprising a surfactant, wherein the ratio of the compound of Formula I, polymer matrix, and surfactant is in a ratio of about 25:65:10.

16. The composition of any one of claims 1 to 15, wherein the composition has a bioavailability of greater than 50%.

17. The composition of claim 16, wherein the composition has a bioavailability of greater than 75%.

18. The composition of claim 17, wherein the composition has a bioavailability of greater than 90%.

19. A method of making an amorphous solid dispersion (ASD), wherein the amorphous solid dispersion comprises a polymer matrix and a compound of Formula I:wherein the method comprises mixing a compound of Formula I with a polymer matrix in a buffer solution.

20. The method of claim 19, wherein the compound of Formula I is present in a form that is substantially not crystalline.

21. The method of claim 20, wherein the buffer solution is phosphate buffer.

22. The method of claim 21, wherein the phosphate buffer is 50 mM phosphate buffer pH 6.8 with 1.0% Tween 80.

23. The method of any one of claims 19 to 22, wherein the compound of Formula I and the polymer matrix is first dissolved in an organic solvent.

24. The method of claim 23, wherein the organic solvent is tetrahydrofuran, dichloromethane, methanol, ethanol, or acetone.

25. The method of claim 23 or 24, wherein the organic solvent is removed, and the buffer solution is added.

26. The method of any one of claims 19 to 25, wherein the polymer matrix is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof.

27. The method of any one of claims 19 to 26, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit LI 00-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit SI 00, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof.

28. The method of any one of claims 19 to 27, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof.

29. The method of any one of claims 19 to 28, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, or a combination thereof.

30. The method of any one of claims 19 to 29, wherein the polymer matrix is HPMCAS M.

31. The method of any one of claims 19 to 30, wherein the amorphous solid dispersion further comprises a surfactant.

32. The method of claim 31, wherein the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof.

33. The method of claim 31 or 32, wherein the surfactant is Kolliphor RH40, TPGS, or a combination thereof.

34. The method of any one of claims 31 to 33, wherein the surfactant is TPGS.

35. The method of any one of claims 31 to 34, wherein the polymer matrix is HPMCAS M and the surfactant is TPGS.

36. The method of any one of claims 19 to 35, wherein the ratio of the compound of Formula I and polymer matrix is about 10:90 to 50:50.

37. The method of claim 36, wherein the ratio of the compound of Formula I and polymer matrix is about 20:80 to 40:60.

38. The method of claim 36 or 37, wherein the ratio of the compound of Formula I and polymer matrix is about 20:80 to 30:70.

39. The method of any one of claims 36 to 38, wherein the ratio of the compound of Formula I, polymer matrix, and surfactant is in a ratio of about 25 :65:10.

40. The method of any one of claims 19 to 38, wherein the composition has a bioavailability of greater than 50%.

41. The method of any one of claims 19 to 40, wherein the composition has a bioavailability of greater than 75%.

42. The method of any one of claims 19 to 41, wherein the composition has a bioavailability of greater than 90%.

43. A compound of Formula I,wherein the compound is prepared from a stable crystalline form, wherein the form of the compound of Formula I in a composition is substantially non-crystalline.

44. The compound of claim 43, wherein the crystalline form is dissolved in an organic solvent with a polymer matrix to form the compound of Formula I, which is substantially non-crystalline.

45. The compound of claim 44, wherein the organic solvent is tetrahydrofuran, dichloromethane, methanol, ethanol, or acetone.

46. The compound of claim 44 or 45, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, or a combination thereof.

47. A composition comprising a polymer matrix and a compound of Formula IERAs pB —R N'R4Formula (II) wherein:RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5-to 12- membered heterocyclyl, optionally substituted C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionallysubstituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with one or more Ci.C6alkyl;RBis hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5 -to 12- membered heterocyclyl, Ce-Ci2aryl, and 5-to 12- membered heteroaryl is optionally substituted with halogen, Ci.Cealkyl, or Ci-Ce alkoxy;R4is hydrogen, halogen, Ci-C6alkyl, -NR4aR4b,-NHC(O)Ci-C6alkyl, -Ci-C6alkylene-O-Ci- Cealkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5-to 6- membered heteroaryl is optionally substituted with Ci-C6alkyl; andR4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-Cealkyl, -C(O)OCi-Cealkyl, optionally substituted C3- C6cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6- Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl; wherein the compound of Formula II is present in a form that is substantially not crystalline.

48. The composition of claim 47, wherein the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Il-a):Formula (Il-a) wherein:R1and R2are independently ethyl or w-propyl;R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;R4is hydrogen, Br, -NR4aR4b, meth oxy methyl, w-butyl, acetamido, pyridin-4-yl, morpholin-R4aand R4bare independently hydrogen, optionally substituted Ci-Cealkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5 - to 12- membered heterocyclyl, C6-Ci2aryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl.

49. The composition of claim 48, wherein R3is F, Cl, Br, methyl, or tri fluoromethyl.

50. The composition of claim 49, wherein R3is Cl or Br.

51. The composition of any one of claims 47 to 50, wherein R4is -NRaRb, pyridin-4-yl, morpholin-4-yl, or52. The composition of claim 51, wherein R4is morpholin-53. The composition of claim 51, wherein R4is -NRaRb, and Raand Rbare independently Ci-C3alkyl.

54. The composition of any one of claims 47 to 53, wherein the compound ofFormula (II) is:or a pharmaceutically acceptable salt thereof.

55. The composition of any one of claims 47 to 53, wherein the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

56. The composition of any one of claims 47 to 53, wherein the compound of Formula (II) is:or a pharmaceutically acceptable salt thereof.

57. The composition of any one of claims 47 to 56, wherein the polymer matrix is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, methyl acrylic acid, polyoxyl 40 castor oil, hypromellose acetate succinate (HPMCAS), or a combination thereof.

58. The composition of any one of claims 47 to 57, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, Soluplus, Eudragit EPO, ethyl cellulose, Poloxamer 407, PVP K30, Poloxamer 188, Eudragit SI 00, Kollidon VA64, HPC Klucel, HPMC E5, HPMC E4M, HPMC El 5, HPMC lOOcP, HPMC-P 55, PVOH or a combination thereof.

59. The composition of claim 58, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, PEG 6000, PEG1500, PC Klucel, HPMC E5, HPMCAS H, or a combination thereof.

60. The composition of claim 59, wherein the polymer matrix is HPMCAS M, HPMCAS L, Kollidon VA64, Eudragit L100, Eudragit L100-55, or a combination thereof.

61. The composition of claim 60, wherein the polymer matrix is HPMCAS M.

62. The composition of any one of claims 47 to 61, wherein the composition further comprises a surfactant.

63. The composition of claim 62, wherein the surfactant is PEG1500, SLS, Kolliphor RH40, TPGS, Poloxamer 407, or a combination thereof.

64. The composition of claim 63, wherein the surfactant is Kolliphor RH40, TPGS, or a combination thereof.

65. The composition of claim 64, wherein the surfactant is TPGS.

66. The composition of any one of claims 62 to 65, wherein the polymer matrix is HPMCAS M and the surfactant is TPGS.

67. The composition of any one of claims 47 to 66, wherein the ratio of the compound of Formula II and polymer matrix is about 10:90 to 50:50.

68. The composition of claim 67, wherein the ratio of the compound of Formula II and polymer matrix is about 20:80 to 40:60.

69. The composition of claim 68, wherein the ratio of the compound of Formula II and polymer matrix is about 20:80 to 30:70.

70. The composition of any one of claims 67 to 69, further comprising a surfactant, wherein the ratio of the compound of Formula II, polymer matrix, and surfactant is in a ratio of about 25:65:10.

71. The composition of any one of claims 47 to 70, wherein the composition has a bioavailability of greater than 50%.

72. The composition of claim 71, wherein the composition has a bioavailability of greater than 75%.

73. The composition of claim 72, wherein the composition has a bioavailability of greater than 90%.

74. A method of treating congenital adrenal hyperplasia (CAH), the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 18 and 47 to 73.

75. A method of treating testicular adrenal rest tumors (TART) or ovarian adrenal rest tumors (OART), the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 18 and 47 to 73.

76. A method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 18 and 47 to 73.

77. A method of treating a neurological disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 18 and 47 to 73.

78. The method of claim 77, wherein the neurological disease or disorder is depression.

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