Methods for preparing heteroaryl-ketone fused azadecaline glucocorticoid receptor modulators

Abstract

The present invention provides methods for preparing heteroaryl-ketone fused azadecaline glucocorticoid receptor modulators and compositions with low levels of impurities.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of foreign priority of International Patent Application No. PCT / CN2020 / 139524, filed December 25, 2020, which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] There are two types of receptors with high affinity for corticosteroids: type I (mineralocorticoid receptor, MR) and type II (glucocorticoid receptor (GR) or cortisol receptor, GR). In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which exhibits both circadian rhythmic changes and elevations in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stressors, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid and acts by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: the 777-amino acid ligand-binding GR-alpha and the GR-beta isoform, which lacks 50 carboxy-terminal residues. Because they contain a ligand-binding domain, GR-beta cannot bind ligand, is constitutively localized in the nucleus, and is transcriptionally inactive. GR is also known as GR-II.

[0003] The biological effects of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists, and antagonists. Several different classes of drugs can block the physiological effects of GR-agonist binding. These antagonists include compounds that bind to GR, thereby inhibiting the ability of agonists to effectively bind to and / or activate GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, with a dissociation constant (K d ) is 10 -9 M (Cadepond (1997) Annu. Rev. Med. 48:129). Relacorilant (CORT-125134) is another such glucocorticoid receptor modulator compound and has previously been described in PCT Publication WO 2013 / 177559 and U.S. Patent No. 8,859,774. What is needed in the art are new methods for preparing relacorilant with reduced impurity content. Surprisingly, the present invention fulfills these and other needs. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, the present invention provides a compound of formula J: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb: [ka] and the following sulfonyl chlorides: [ka] to prepare a compound of formula J in at least 60% yield and at least 98% purity; During the ceremony, X 1 is -CH= or -N=, HX is an acid solvate, The subscript n is 1 to 4.

[0005] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula I in at least 60% yield and at least 98% purity; During the ceremony, HX is an acid solvate, The subscript n is 1 to 4.

[0006] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-1: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: [ka] wherein the subscript n is 1 to 4.

[0007] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) (i) a first mobile phase mixture comprising water in an amount of at least 95% (v / v), formic acid in an amount of 0.05-0.2% (v / v), and acetonitrile in an amount of 1-5% (v / v); (ii) a second mobile phase mixture comprising water in an amount of 45-55% (v / v), formic acid in an amount of 0.01-0.1% (v / v), and acetonitrile in an amount of 45-55% (v / v); and (iii) eluting the compound of Formula I by high performance liquid chromatography on a C18 column using a third mobile phase comprising water in an amount of 5 to 15% (v / v), formic acid in an amount of 0.005 to 0.02% (v / v), and acetonitrile in an amount of at least 85% (v / v); forming an elution mixture comprising a compound of formula I having a purity of at least 98% and a compound of formula X-5 below in an amount of less than 0.75% (w / w); [ka] (a1) extracting the compound of Formula I from the elution mixture into ethyl acetate to form an extraction mixture; (a2) mixing the extraction mixture with methyl t-butyl ether (MTBE) under vacuum to form an MTBE mixture containing less than 5% (v / v) ethyl acetate; (d) filtering the MTBE mixture through a filter to remove the compound of formula I, a compound of formula X-5 in an amount of less than 0.5% (w / w), a compound of formula X-4 in an amount of less than 0.3% (w / w): [ka] and less than 0.25% (w / w) of a compound of formula X-6: [ka] forming a filtered MTBE mixture comprising: (e) adding the filtered MTBE mixture to heptane to form a precipitated compound of Formula I containing less than 20 ppm of 1,4-dibromopentane; (f) dissolving the precipitated compound of Formula I in methanol to form a methanol mixture; (g) adding the methanol mixture to water to precipitate the purified compound of Formula I, wherein the purified compound of Formula I has a purity of at least 99%; and a compound of formula X-5 in an amount of less than 0.5% (w / w); 1,4-dibromopentane in an amount less than 6 ppm; Less than 6 ppm of the following: methyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] and precipitating the purified compound of Formula I, wherein the purified compound contains less than 6 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. [ka]

[0008] In some embodiments, the present invention provides a compound of formula IIa: [ka] 1. A method for preparing (c) a Grignard reagent, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of 1.0 to 1.5 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 relative to the compound of formula III, thereby preparing a compound of formula IIa.

[0009] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-2: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula I in at least 75% yield and at least 98% purity; During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0010] In some embodiments, the present invention provides a compound of formula IIb-2: [ka] 1. A method for preparing (b) a compound of formula IIa: [ka] and sulfonic acids of the formula: [ka] forming a fifth reaction mixture comprising: During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0011] In some embodiments, the present invention provides a method for treating a cancer cell comprising: in an amount of at least 99% (w / w) of a compound of formula I: [ka] and one or more impurities in an amount of 0.01 to 1% (w / w).

[0012] In some embodiments, the present invention provides the following crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate: [ka] It is characterized by an X-ray powder diffraction (XRPD) pattern with peaks at about 18.2°, 18.3°, and 19.7° 2-θ±0.2° 2-θ. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows a synthetic scheme for preparing (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate relacorilant according to Example 3.

[0014] [Figure 2] FIG. 2 shows the powder X-ray diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate.

[0015] [Figure 3] FIG. 3 shows the differential scanning calorimetry (DSC) thermoanalysis curve of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate.

[0016] [Figure 4] FIG. 4 shows the thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate.

[0017] [Figure 5]FIG. 5 shows the powder X-ray diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-oxalate.

[0018] [Figure 6] FIG. 6 shows the differential scanning calorimetry (DSC) thermoanalysis curve of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-oxalate.

[0019] [Figure 7] FIG. 7 shows the thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-oxalate.

[0020] [Figure 8] FIG. 8 shows the powder X-ray diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrochloride.

[0021] [Figure 9] FIG. 9 shows the differential scanning calorimetry (DSC) thermoanalysis curve of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrochloride.

[0022] [Figure 10]FIG. 10 shows the thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrochloride. DETAILED DESCRIPTION OF THE INVENTION

[0023] I. General The present disclosure describes a novel method for preparing the compound of formula I, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (relacorilant), which has lower levels of impurities than previously described methods. Relacorilant can also be named (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone as found in Example 18 of U.S. Pat. No. 8,859,774. The present disclosure also describes compositions of relacorilant with lower impurity concentrations.

[0024] II. Definition "About," when referring to a value, includes the stated value plus or minus 10% of the stated value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to the stated value at each of the upper and lower limits of that range plus or minus 10% of the stated value. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0025] "Forming a reaction mixture" refers to the process of contacting at least two separate species so that they can be mixed together and react. However, it will be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0026] "Dissolve," "dissolving," or "dissolution" refers to a solid material that is substantially soluble in a particular solvent. For example, a solid material can be greater than 90% soluble in a solvent, or greater than 91, 92, 93, 94, 95, 96, 97, 98, or 99% soluble in a solvent.

[0027] "Distilling," "distilling," or "distillation" refers to the separation of components in a liquid mixture using a combination of temperature and pressure to convert the desired component from a liquid to a gas, which then condenses back to a liquid, separating the desired component from the other components of the mixture.

[0028] "Eluting," "eluting," or "elution" refers to the process of separating a component of interest from other components in a mixture by passing the mixture over a stationary phase. The component of interest is eluted from the stationary phase using a mobile phase, which may contain any suitable solvent or acid.

[0029] "Precipitate," "precipitated," or "precipitation" refers to the formation of a solid from a solution, such as by adding a first solvent in which a compound is soluble to an excess of a second solvent in which the compound is not substantially soluble, such that the dissolved compound emerges from solution to form a solid.

[0030] By "substantially free" it is meant a composition having less than 5%, less than 1%, less than 0.5%, or even less than 0.1% by weight of undesirable components.

[0031] "Aqueous phase" refers to a mixture that contains water.

[0032] "Organic phase" refers to a mixture containing a water-miscible or water-immiscible solvent capable of dissolving either or both water-soluble and water-insoluble organic compounds. The organic phase of the present invention can be formed from one or more organic solvents. Exemplary organic solvents can include non-polar aprotic solvents, polar aprotic solvents, and polar protic solvents. Representative solvents include, but are not limited to, pentane, hexanes, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, chloroform, and the like.

[0033] "Acid" is defined as a group of protons (H + ) or a compound that is an electron pair acceptor according to the Lewis definition. Acids useful in the present invention include, but are not limited to, alkanoic or carboxylic acids (such as formic acid, acetic acid, citric acid, lactic acid, and oxalic acid), sulfonic acids, and mineral acids, as described herein. Mineral acids are inorganic acids such as hydrogen halides (such as hydrofluoric acid, hydrochloric acid, and hydrobromice acid), halogen oxoacids (such as hypochlorous acid and perchloric acid), and sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfonic acids include, among others, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonic acid, and camphorsulfonic acid.

[0034] "Grignard reagent" refers to a reagent containing a complex of magnesium metal, a halide, and an alkyl ligand capable of forming a carbon-carbon bond. Exemplary Grignard reagents include, but are not limited to, iPrMgCl and iPrMgBr.

[0035] "Non-nucleophilic base" refers to a base that is a medium to strong base but at the same time has poor nucleophilicity. Representative non-nucleophilic bases include bases such as potassium carbonate, sodium carbonate, potassium t-butoxide, and sodium t-butoxide, as well as amine bases such as triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. This includes non-nucleophilic amine bases.

[0036] A "solvent" refers to a substance, e.g., a liquid, capable of dissolving a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having a proton available for removal, e.g., a hydroxyl or carboxyl group. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (e.g., methanol, ethanol, propanol, isopropanol), acids (e.g., formic acid, acetic acid), and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents are useful in the present invention.

[0037] "Room temperature" is the range of temperatures generally considered suitable for human habitation, i.e., between approximately 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0038] "Vacuum" or "reduced pressure" refers to a pressure that is less than atmospheric pressure. Atmospheric pressure is measured as approximately 1013 mbar, 760 mmHg, or approximately 14.7 psi. Thus, a vacuum can be less than 1013 mbar, or less than 100, 10, 1, 0.1 mbar, or less than 0.01 mbar.

[0039] "Alkyl" refers to a straight or branched saturated aliphatic group having the number of carbon atoms indicated. Alkyl includes, for example, C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 It may contain any number of carbons, such as C 1~6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0040] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0041] "Haloalkyl" refers to an alkyl as defined above, in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to alkyl groups, haloalkyl groups include, for example, C 1~6and the like. For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. The term "perfluoro" can be used to refer to a compound or group in which all hydrogens have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0042] "Pharmaceutically acceptable salt" refers to the acid salt or base salt of the compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0043] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0044] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and its absorption by the subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavoring agents, and coloring agents. One skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0045] "Treate," "treating," and "treatment" refer to any indication of successful treatment or amelioration of an injury, condition, or state, including any objective or subjective parameter, such as relief, remission, or a decrease in symptoms or damage, a condition or state becoming more tolerable to the patient, a slowing of the rate of degeneration or decline, a decline in the end point of degeneration, or an improvement in the patient's physical or mental well-being. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0046] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0047] "Patient" or "subject" refers to a living organism suffering from or prone to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammalian animals. In some embodiments, the patient is a human.

[0048] A "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0049] "Glucocorticoid receptor" ("GR") refers to one of a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also called the cortisol receptor. This term includes GR, recombinant GR, and mutant GR isoforms.

[0050] The cortisol receptor is a glucocorticoid receptor (GR), in particular a type II GR, which specifically binds cortisol and / or cortisol analogues, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0051] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (type I GR), which is activated by aldosterone in humans.

[0052] " Glucocorticoid receptor modulator " (GRM) refers to any compound that modulates any biological response associated with the binding of glucocorticoid receptor to agonist. As used herein, with respect to GRM, the glucocorticoid receptor may be GR, or both. For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRM acting as an antagonist, such as mifepristone, inhibits the agonist-induced increase in the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J.Med.Chem., 2004, 47, 2441-2452.

[0053] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRA, the glucocorticoid receptor may be GR, or both. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity can be measured as reviewed in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Inhibitors have an IC of less than 10 micromolar. 50 (half maximal inhibitory concentration). See Example 1 of U.S. Patent No. 8,685,973, the entire contents of which are incorporated herein by reference in their entirety.

[0054] "Modulate" and "modulating" are used according to their ordinary meaning and refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, when used in reference to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0055] "Modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of the molecule's target.

[0056] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist to a receptor molecule or inhibiting the receptor-agonist signal. Receptor antagonists inhibit or suppress agonist-mediated responses, such as gene expression.

[0057] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. An antagonist can inhibit expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or less compared to a control in the absence of the antagonist. In some embodiments, inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more than expression or activity in the absence of the antagonist.

[0058] "Inhibition," "inhibit," and "inhibitor" refer to a compound that inhibits a particular action or function or a method of inhibiting a particular action or function.

[0059] "Disorder" or "condition" refers to a condition or state of health of a patient or subject that can be treated with a glucocorticoid receptor modulator of the present invention. In some embodiments, examples of disorders or conditions include, but are not limited to, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and antipsychotic-induced weight gain.

[0060] "Fatty liver disease" refers to a disease or condition that is at least partially caused by abnormal liver lipid accumulation.Fatty liver disease includes, for example, alcoholic fatty liver disease, non-alcoholic fatty liver disease, and acute fatty liver of pregnancy.Fatty liver disease can be, for example, macrovesicular steatosis or microvesicular steatosis.

[0061] "Nonalcoholic fatty liver disease" ("NAFLD") refers to a type of fatty liver disease that occurs when fat accumulates in the liver (steatosis) due to causes other than excessive alcohol use. NAFLD is thought to cover a spectrum of disease activity. This spectrum begins as fat accumulation (steatosis) in the liver. The majority of patients with NAFLD have few or no symptoms. Patients may complain of fatigue, lethargy, and a dull discomfort in the right upper abdomen. Mild eczema may be noticed, but this is rare. More commonly, NAFLD is diagnosed after abnormal liver function tests during routine blood work. By definition, alcohol consumption greater than 20 g / day (approximately 25 ml / day of net ethanol) excludes this condition.

[0062] "Non-alcoholic steatohepatitis" ("NASH") refers to the most extreme form of NAFLD. NAFLD can progress to non-alcoholic steatohepatitis (NASH), a condition in which steatosis is combined with inflammation and fibrosis (steatohepatitis). NASH is a progressive disease. Over a 10-year period, up to 20% of patients with NASH will develop cirrhosis, and 10% will experience liver disease-related death.

[0063] "Substance use disorder" refers to the compulsive use of a substance despite unpleasant or harmful consequences of that use. Substance use disorders can include impaired control (e.g., using excessive amounts of the substance or using it for a longer period than originally intended), social impairment (e.g., failing to fulfill primary role obligations at work, school, or home), risky use (e.g., repeated use of the substance in physically hazardous situations), and pharmacological criteria (e.g., tolerance or withdrawal). Substance use disorders were previously called "addictions" but are now classified as: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders (5th Edition, DSM-5) Since the publication of the DSM-V (hereafter "DSM-V"), the terms "addiction" and "addict" have been replaced with the terms "substance use disorder" (replacing "addict") and person with a substance use disorder (replacing "addict"). A person with a substance use disorder may be referred to as having a substance use disorder related to a particular substance, but prior to the publication of DSM-V, such a person may have been described as being "dependent on" that substance. For example, if a person has a substance use disorder related to a stimulant drug, the person may have been described as being "dependent on" that stimulant drug prior to the publication of DSM-V.

[0064] "Substance," when described with phrases such as "substance use disorder for the substance" and "substance use disorder for the substance," refers to a substance that a patient craves or uses compulsively despite the unpleasant or harmful consequences of its use. Thus, such a "substance" is a substance used, ingested, or otherwise administered (including self-administered) by a person with a substance use disorder for that substance. The terms "substance addiction" and "substance abuse" may have previously been used to refer to such substances, and the substances may have previously been called "addictive substances" (e.g., prior to publication of DSM-V).

[0065] A "person suffering from a substance use disorder" refers to a person who has a substance use disorder involving a specific substance, or possibly multiple specific substances. Such a "substance" may be a drug, or alcohol, or tobacco, or any other substance that a person may ingest. For example, such a "substance" may be alcohol, a stimulant, an opioid, or other substance.

[0066] III. Method for preparing formula I from formula IIb-1 The present invention relates to a compound of formula J: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb: [ka] and the following sulfonyl chlorides: [ka] to prepare a compound of formula J in at least 60% yield and at least 98% purity; During the ceremony, X 1 is -CH= or -N=, HX is an acid solvate, The subscript n is 1 to 4.

[0067] In some embodiments, X of formula J 1 is -CH=.

[0068] The present invention provides a compound of formula I: (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone relacorilant; [ka] and the compound of formula Ia below, (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, [ka] A method for preparing the compound is provided.

[0069] The compound of Formula I (relacorilant, CORT125134) and the compound of Formula Ia are described in PCT Publication WO 2013 / 177559 and U.S. Pat. No. 8,859,774.

[0070] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula I in at least 60% yield and at least 98% purity; During the ceremony, HX is an acid solvate, The subscript n is 1 to 4.

[0071] In some embodiments, HX is HCl, HBr, [ka] and R 1 is C 1~6 Alkyl, C 1~10 It is haloalkyl, phenyl, or 4-methylphenyl.

[0072] In some embodiments, the compound of Formula IIb can have the structure: [ka] where the subscript n is 1 to 4.

[0073] In some embodiments, the compound of Formula IIb can have the structure: [ka] where the subscript n is 1 to 4.

[0074] In some embodiments, the compound of Formula IIb can have the structure: [ka] R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl, where the subscript n is 1 to 4.

[0075] In some embodiments, the compound of Formula IIb can have the structure: [ka] where the subscript n is 1 to 4.

[0076] In some embodiments, the compound of Formula IIb can have the structure: [ka] R 1is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl, where the subscript n is 1 to 4.

[0077] In some embodiments, the compound of Formula IIb can have the structure: [ka] R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl, where the subscript n is 1 to 4.

[0078] A. Preparation of Formula I from Formula IIb-1 In some embodiments, HX is HBr. The compound of formula I can be prepared from a compound of formula IIb-1: [ka] It can be prepared by

[0079] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-1: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: [ka] wherein the subscript n is 1 to 4.

[0080] The subscript n can be 1, 1.5, 2, 2.5, 3, 3.5, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of Formula IIb-1 has the following structure: [ka]

[0081] In some embodiments, the first reaction mixture further comprises a non-nucleophilic amine base. Any suitable non-nucleophilic amine base can be used in the first reaction mixture. In some embodiments, the non-nucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof. In some embodiments, the non-nucleophilic amine base comprises triethylamine.

[0082] The first reaction mixture can include any suitable solvent. For example, the solvent can be an organic solvent, including, but not limited to, ethyl acetate, isopropyl acetate, and n-butyl acetate. In some embodiments, the first reaction mixture further includes a first solvent. In some embodiments, the first solvent includes ethyl acetate, isopropyl acetate, or n-butyl acetate. In some embodiments, the first reaction mixture further includes isopropyl acetate.

[0083] The sulfonyl chloride used in the first reaction mixture can be present in any suitable molar ratio relative to the compound of Formula IIb-1. For example, the sulfonyl chloride can be present in a molar ratio of 1.0 to 3.0 relative to the compound of Formula IIb-1, 1.0 to 2.5, 1.0 to 2.0, 1.0 to 1.5, 1.1 to 2.4, or 1.2 to 2.3 relative to the compound of Formula IIb-1. In some embodiments, the sulfonyl chloride can be present in a molar ratio of 1.2 to 2.3 relative to the compound of Formula IIb-1. The sulfonyl chloride can be present in a molar ratio of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, or 2.3 relative to the compound of Formula IIb-1. In some embodiments, the sulfonyl chloride can be present in a molar ratio of about 1.2 relative to the compound of Formula IIb-1.

[0084] The compound of formula I can be prepared in any suitable yield. For example, the compound of formula I can be prepared in a yield of at least 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, or at least 95%. In some embodiments, the compound of formula I can be prepared in a yield of at least 60%.

[0085] The compound of Formula I can be prepared with any suitable purity. For example, the compound of Formula I can be prepared with a purity of at least 90%, or 91, 92, 93, 94, 95, 96, 97, 98, or at least 99%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 96%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 97%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 98%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 99%.

[0086] The compound of formula I can be prepared with any acceptable amount of the compound of formula X-4 below. [ka] For example, a compound of Formula I may be prepared to contain less than 5% (w / w), or less than 4, 3, 2, 1, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1% (w / w) of a compound of Formula X-4. In some embodiments, a compound of Formula I may be prepared to contain less than 0.5% (w / w) of a compound of Formula X-4. In some embodiments, a compound of Formula I may be prepared to contain less than 0.3% (w / w) of a compound of Formula X-4. In some embodiments, a compound of Formula I may be prepared to contain less than 0.1% (w / w) of a compound of Formula X-4.

[0087] The compound of Formula I can be prepared with any acceptable amount of the compound of Formula X-5. For example, the compound of Formula I can be prepared to contain less than 5% (w / w), or less than 4, 3, 2, 1, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I can be prepared to contain less than 1% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I can be prepared to contain less than 0.75% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I can be prepared to contain less than 0.5% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I can be prepared to contain less than 0.2% (w / w) of the compound of Formula X-5.

[0088] The compound of formula I can be prepared with any acceptable amount of the compound of formula X-6 below. [ka] For example, a compound of Formula I may be prepared to contain less than 5% (w / w), or less than 4, 3, 2, 1, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1% (w / w) of a compound of Formula X-6. In some embodiments, a compound of Formula I may be prepared to contain less than 0.25% (w / w) of a compound of Formula X-6. In some embodiments, a compound of Formula I may be prepared to contain less than 0.2% (w / w) of a compound of Formula X-6. In some embodiments, a compound of Formula I may be prepared to contain less than 0.1% (w / w) of a compound of Formula X-6.

[0089] The compound of Formula I may be prepared with 1,4-dibromopentane in an amount less than 10 ppm. For example, the compound of Formula I may be prepared with 1,4-dibromopentane in an amount less than 10 ppm, or less than 10, 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, the compound of Formula I may be prepared with 1,4-dibromopentane in an amount less than 8 ppm. In some embodiments, the compound of Formula I may be prepared with 1,4-dibromopentane in an amount less than 6 ppm. In some embodiments, the compound of Formula I may be prepared with 1,4-dibromopentane in an amount less than 4 ppm.

[0090] The compound of formula I may be present in an amount of less than 10 ppm of the following: methyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] For example, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-methyl sulfonate that is less than 10 ppm, or less than 10, 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-methyl sulfonate that is less than 8 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-methyl sulfonate that is less than 6 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-methyl sulfonate that is less than 4 ppm.

[0091] The compound of formula I may be present in an amount of less than 10 ppm of the following: ethyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] For example, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-ethyl sulfonate that is less than 10 ppm, or less than 10, 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-ethyl sulfonate that is less than 8 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-ethyl sulfonate that is less than 6 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-ethyl sulfonate that is less than 4 ppm.

[0092] The compound of formula I may be present in an amount of less than 10 ppm of the following: isopropyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] For example, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-isopropyl sulfonate that is less than 10 ppm, or less than 10, 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-isopropyl sulfonate that is less than 8 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-isopropyl sulfonate that is less than 6 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-isopropyl sulfonate that is less than 4 ppm.

[0093] The compound of formula I may be present in an amount of less than 10 ppm of the following: 1-methyl-1H-pyrazole-4-sulfonyl chloride, [ka] For example, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-sulfonyl chloride that is less than 10 ppm, or less than 10, 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-sulfonyl chloride that is less than 8 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-sulfonyl chloride that is less than 6 ppm. In some embodiments, the compound of Formula I may be prepared with an amount of 1-methyl-1H-pyrazole-4-sulfonyl chloride that is less than 4 ppm.

[0094] In some embodiments, the method for preparing a compound of formula I comprises: (a) a compound of formula IIb-1, triethylamine, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a molar ratio of about 1.2 to the compound of formula IIb-1, to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: [ka]

[0095] In some embodiments, the method of preparing a compound of formula I also includes, after step (a), (a1) combining a first reaction mixture with water having a pH of 4-5 to form a first organic phase and a first aqueous phase; (a2) mixing the first organic phase with water and sodium chloride having a pH of 5-6; (a3) mixing the first organic phase with silica gel.

[0096] The organic phase can comprise any suitable organic solvent. In some embodiments, the first organic phase comprises a first solvent.

[0097] Any suitable silica gel can be used in the methods of the present invention. Exemplary silica gels include, but are not limited to, 200-300 mesh silica gel, 60-80 mesh, 80-120 mesh, 100-200 mesh, etc. In some embodiments, the silica gel is 200-300 mesh silica gel.

[0098] B. Preparation of Formula IIb-1 from Formula IIa The compound of formula IIb-1 can be prepared by a variety of methods. In some embodiments, the compound of formula IIb-1 is (b) a compound of formula IIa: [ka] and gaseous HBr to form a compound of Formula IIb-1, having the following structure: [ka]

[0099] The gaseous HBr can be present at any suitable partial pressure.

[0100] The second reaction mixture may also include a second solvent. The second solvent may be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene. In some embodiments, the second reaction mixture further includes a second solvent. In some embodiments, the second solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene. In some embodiments, the second reaction mixture further includes toluene.

[0101] The compound of formula I can be prepared from a compound of formula IIa. The compound of formula IIa corresponds to intermediate 29 of U.S. Pat. No. 8,859,974, 1-(4-chlorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (R)-tert-butyl. The compound of formula IIa can also be named (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylate. In some embodiments, the compound of formula I is (b) a compound of formula IIa: [ka] and gaseous HBr to form a compound of formula IIb-1 having the structure: [ka] (a) a compound of formula IIb-1: triethylamine, and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a molar ratio of about 1.2 relative to the compound of Formula IIb-1; (a1) combining a first reaction mixture with water having a pH of 4-5 to form a first organic phase and a first aqueous phase; (a2) mixing the first organic phase with water and sodium chloride having a pH of 5-6; (a3) mixing the first organic phase and silica gel to prepare the compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of the compound of formula X-5: [ka]

[0102] C. Preparation of Formula IIa from Formula III The compound of formula IIa can be prepared by any suitable method. In some embodiments, the compound of formula IIa is (c) a Grignard reagent, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of 1.0 to 1.5 relative to the compound of formula III, and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 relative to the compound of formula III, thereby preparing a compound of formula IIa.

[0103] Further embodiments for the preparation of compounds of formula IIa are described below in Section IV.

[0104] In some embodiments, the method for preparing a compound of formula I comprises: (c) iPrMgBr, 2-methyltetrahydrofuran, toluene, and a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of about 1.4 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of about 1.65 relative to the compound of formula III to prepare a compound of formula IIa: [ka] (c1) adding acetic acid and water to the third reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa, 2-methyltetrahydrofuran in an amount of less than 100 ppm, and water in an amount of less than 0.5% (w / w); (b) forming a second reaction mixture comprising the intermediate mixture and gaseous HBr to form a compound of formula IIb-1 having the structure: [ka] (a) a compound of formula IIb-1, triethylamine, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a molar ratio of about 1.2 to the compound of formula IIb-1, to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: [ka]

[0105] In some embodiments, the method of preparing a compound of formula I comprises, after step (a), (a1) combining a first reaction mixture with water having a pH of 4-5 to form a first organic phase and a first aqueous phase; (a2) mixing the first organic phase with water and sodium chloride having a pH of 5-6; (a3) mixing the first organic phase with silica gel.

[0106] D. Purification of the Compound of Formula I The compound of formula I can be purified by a variety of methods. In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) (i) a first mobile phase mixture comprising water in an amount of at least 95% (v / v), formic acid in an amount of 0.05-0.2% (v / v), and acetonitrile in an amount of 1-5% (v / v); (ii) a second mobile phase mixture comprising water in an amount of 45-55% (v / v), formic acid in an amount of 0.01-0.1% (v / v), and acetonitrile in an amount of 45-55% (v / v); and (iii) eluting the compound of Formula I by high performance liquid chromatography on a C18 column using a third mobile phase comprising water in an amount of 5 to 15% (v / v), formic acid in an amount of 0.005 to 0.02% (v / v), and acetonitrile in an amount of at least 85% (v / v); forming an elution mixture comprising a compound of formula I having a purity of at least 98% and a compound of formula X-5 below in an amount of less than 0.75% (w / w); [ka] (a1) extracting the compound of Formula I from the elution mixture into ethyl acetate to form an extraction mixture; (a2) mixing the extraction mixture with methyl t-butyl ether (MTBE) under vacuum to form an MTBE mixture containing less than 5% (v / v) ethyl acetate; (d) filtering the MTBE mixture through a filter to remove the compound of formula I, a compound of formula X-5 in an amount of less than 0.5% (w / w), a compound of formula X-4 in an amount of less than 0.3% (w / w): [ka] and less than 0.25% (w / w) of a compound of formula X-6: [ka] forming a filtered MTBE mixture comprising: (e) adding the filtered MTBE mixture to heptane to form a precipitated compound of Formula I containing 1,4-dibromopentane in an amount less than 20 ppm; (f) dissolving the precipitated compound of Formula I in methanol to form a methanol mixture; (g) adding the methanol mixture to water to precipitate the purified compound of Formula I, wherein the purified compound of Formula I has a purity of at least 99%; and a compound of formula X-5 in an amount of less than 0.5% (w / w); 1,4-dibromopentane in an amount less than 6 ppm; Less than 6 ppm of the following: methyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] and precipitating the purified compound of Formula I, wherein the purified compound contains less than 6 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. [ka]

[0107] Any suitable filter can be used in the purification method of the present invention. For example, the filter can be a cartridge filter. In some embodiments, the filter can be a CUNO cartridge filter.

[0108] In some embodiments, the purified compound of Formula I has a purity of at least 99% and contains 1,4-dibromopentane in an amount less than 8 ppm.

[0109] In some embodiments, the purified compound of Formula I has a purity of at least 99% and further comprises methyl bromide in an amount less than 20 ppm and 2-bromopropane in an amount less than 20 ppm. In some embodiments, the purified compound of Formula I has a purity of at least 99% and further comprises methyl bromide in an amount less than 8 ppm and 2-bromopropane in an amount less than 8 ppm. In some embodiments, the purified compound of Formula I has a purity of at least 99% and further comprises methyl bromide in an amount less than 8 ppm, 2-bromopropane in an amount less than 8 ppm, and 1,4-dibromopentane in an amount less than 8 ppm.

[0110] In some embodiments, the purified compound of Formula I has a purity of at least 99%; and a compound of formula X-4 in an amount of less than 0.1% (w / w), a compound of formula X-5 in an amount of less than 0.2% (w / w); a compound of formula X-6 in an amount of less than 0.2% (w / w); 1,4-dibromopentane in an amount less than 4 ppm; 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm, and Contains less than 4 ppm of methyl 1-methyl-1H-pyrazole-4-sulfonate.

[0111] In some embodiments, the purified compound of Formula I has a purity of at least 99%; and Less than 6 ppm of the following: ethyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] and further containing less than 6 ppm of the following: isopropyl 1-methyl-1H-pyrazole-4-sulfonate. [ka]

[0112] In some embodiments, the purified compound of Formula I has a purity of at least 99%; and a compound of formula X-4 in an amount of less than 0.1% (w / w), a compound of formula X-5 in an amount of less than 0.2% (w / w); a compound of formula X-6 in an amount of less than 0.2% (w / w); Methyl bromide in an amount less than 4 ppm; 2-bromopropane in an amount less than 4 ppm; 1,4-dibromopentane in an amount less than 4 ppm; 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm; Methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm; Ethyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm; Further included isopropyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm.

[0113] The compounds of formula I purified by the above methods may be prepared by the above methods.

[0114] IV. Method for preparing formula IIA from formula III The compound of formula IIa can be prepared by any suitable method. In some embodiments, the present invention provides a compound of formula IIa: [ka] 1. A method for preparing (c) a Grignard reagent, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of 1.0 to 1.5 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 relative to the compound of formula III, thereby preparing a compound of formula IIa.

[0115] The Grignard reagent can be any suitable Grignard reagent. In some embodiments, the Grignard reagent comprises iPrMgCl or iPrMgBr. In some embodiments, the Grignard reagent comprises iPrMgBr.

[0116] The Grignard reagent can be present in any suitable molar ratio relative to the compound of Formula III. For example, the Grignard reagent can be present in a molar ratio of 1.0 to 2.0, or 1.1 to 1.9, 1.2 to 1.8, 1.3 to 1.8, 1.4 to 1.7, 1.5 to 1.7, or 1.6 to 1.7 relative to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 1.5 to 1.7 relative to the compound of Formula III. The Grignard reagent can be present in a molar ratio of about 1.5, or about 1.55, 1.60, 1.65, 1.70, or about 1.75 relative to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 1.65 relative to the compound of Formula III.

[0117] The pyridine may be present in any suitable ratio relative to the compound of Formula III. For example, the pyridine may be present in a molar ratio of 1.0 to 2.0, or 1.0 to 1.9, 1.0 to 1.8, 1.0 to 1.7, 1.0 to 1.6, 1.0 to 1.5, 1.1 to 1.5, 1.2 to 1.5, or 1.3 to 1.5 relative to the compound of Formula III. The pyridine may be present in a molar ratio of about 1.0, or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or about 2.0 relative to the compound of Formula III. In some embodiments, the pyridine may be present in a molar ratio of about 1.4 relative to the compound of Formula III.

[0118] The third reaction mixture may also include a third solvent. The third solvent may be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or a combination thereof. In some embodiments, the third reaction mixture further includes a third solvent. In some embodiments, the third solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or a combination thereof. In some embodiments, the third reaction mixture further includes 2-methyltetrahydrofuran and toluene.

[0119] In some embodiments, the method of preparing the compound of Formula IIa also includes (c1) adding an acid and water to the third reaction mixture to form a work-up mixture, and (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa, 2-methyltetrahydrofuran in an amount of less than 200 ppm, and water in an amount of less than 0.5% (w / w).

[0120] The acid in step (c1) can be any suitable acid. In some embodiments, the acid comprises formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or a mixture thereof. In some embodiments, the acid comprises acetic acid.

[0121] The intermediate mixture can include 2-methyltetrahydrofuran in any amount less than 200 ppm. For example, the intermediate mixture can include 2-methyltetrahydrofuran in an amount less than 200 ppm, or less than 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 ppm. In some embodiments, the intermediate mixture can include 2-methyltetrahydrofuran in an amount less than 100 ppm.

[0122] In some embodiments, the method for preparing a compound of Formula IIa comprises: (c) iPrMgBr, 2-methyltetrahydrofuran, toluene, and a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of about 1.4 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of about 1.65 relative to the compound of formula III to prepare a compound of formula IIa: [ka] (c1) adding acetic acid and water to the third reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa, 2-methyltetrahydrofuran in an amount of less than 100 ppm, and water in an amount of less than 0.5% (w / w).

[0123] V. Method for preparing formula J from formula IIB-2 In some embodiments, HX is [ka] where: R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0124] In some embodiments, a compound of formula J: [ka] or a pharmaceutically acceptable salt thereof, (a) a compound of formula IIb-2: [ka] and the following sulfonyl chlorides: [ka] to prepare a compound of formula J in at least 75% yield and at least 98% purity; During the ceremony, X 1 is -CH= or -N=, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0125] In some embodiments, a compound of Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, (a) a compound of formula IIb-2: [ka] and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula Ia in at least 75% yield and at least 98% purity; During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0126] In some embodiments, the compound of formula I contains less than 1% (w / w) of a compound of formula X-5a: [ka]

[0127] Compounds of formula I can be prepared from compounds of formula IIb-2 below. [ka]

[0128] A. Preparation of Formula J from Formula IIb-2 In some embodiments, the present invention provides a compound of formula J: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-2: [ka] and the following sulfonyl chlorides: [ka] to prepare a compound of formula J in at least 75% yield and at least 98% purity; During the ceremony, X 1 is -CH= or -N=, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0129] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-2: [ka] and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula I in at least 75% yield and at least 98% purity; During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0130] In some embodiments, the present invention provides a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb-2: [ka] and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: [ka] to prepare a compound of Formula Ia in at least 75% yield and at least 98% purity; During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0131] In some embodiments, R 1 is C 1~2 Alkyl, C 1~2 haloalkyl, phenyl, or 4-methylphenyl. In some embodiments, R 1 is methyl, ethyl, —CF, phenyl, or 4-methylphenyl. In some embodiments, R 1 is methyl.

[0132] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of Formula IIb-2 can have the following structure: [ka]

[0133] In some embodiments, the fourth reaction mixture further comprises a non-nucleophilic amine base. Any suitable non-nucleophilic amine base can be used in the fourth reaction mixture. In some embodiments, the non-nucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof. In some embodiments, the non-nucleophilic amine base comprises triethylamine.

[0134] The fourth reaction mixture can include any suitable solvent. For example, the solvent can be an organic solvent, including, but not limited to, ethyl acetate, isopropyl acetate, and n-butyl acetate. In some embodiments, the fourth reaction mixture further includes a fourth solvent. In some embodiments, the fourth solvent includes ethyl acetate, isopropyl acetate, n-butyl acetate, or a mixture thereof. In some embodiments, the fourth reaction mixture further includes ethyl acetate.

[0135] The sulfonyl chloride used in the fourth reaction mixture can be present in any suitable molar ratio relative to the compound of Formula IIb-2. For example, the sulfonyl chloride can be present in a molar ratio of 0.5 to 2.0 relative to the compound of Formula IIb-2, or a molar ratio of 0.5 to 1.5, 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, or 0.9 to 1.1 relative to the compound of Formula IIb-2. In some embodiments, the sulfonyl chloride can be present in a molar ratio of 0.5 to 1.5 relative to the compound of Formula IIb-2. The sulfonyl chloride can be present in a molar ratio of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 relative to the compound of Formula IIb-2. In some embodiments, the sulfonyl chloride can be present in a molar ratio of about 1.0 relative to the compound of Formula IIb-2.

[0136] The compound of Formula J, Formula I, or Formula Ia can be prepared in any suitable yield. For example, the compound of Formula J, Formula I, or Formula Ia can be prepared in a yield of at least 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, or at least 95%. In some embodiments, the compound of Formula J, Formula I, or Formula Ia can be prepared in a yield of at least 75%.

[0137] The compound of formula I can be prepared in any suitable yield. For example, the compound of formula I can be prepared in a yield of at least 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, or at least 95%. In some embodiments, the compound of formula I can be prepared in a yield of at least 75%.

[0138] The compound of Formula J, Formula I, or Formula Ia can be prepared with any suitable purity. For example, the compound of Formula J, Formula I, or Formula Ia can be prepared with a purity of at least 90%, or 91, 92, 93, 94, 95, 96, 97, 98, or at least 99%. In some embodiments, the compound of Formula J, Formula I, or Formula Ia can be prepared with a purity of at least 96%. In some embodiments, the compound of Formula J, Formula I, or Formula Ia can be prepared with a purity of at least 97%. In some embodiments, the compound of Formula J, Formula I, or Formula Ia can be prepared with a purity of at least 98%. In some embodiments, the compound of Formula J, Formula I, or Formula Ia can be prepared with a purity of at least 99%.

[0139] The compound of Formula I can be prepared with any suitable purity. For example, the compound of Formula I can be prepared with a purity of at least 90%, or 91, 92, 93, 94, 95, 96, 97, 98, or at least 99%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 96%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 97%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 98%. In some embodiments, the compound of Formula I can be prepared with a purity of at least 99%.

[0140] In some embodiments, the method of preparing a compound of Formula J, Formula I, or Formula Ia comprises: (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the fourth reaction mixture to precipitate the compound of Formula J, Formula I, or Formula Ia.

[0141] In some embodiments, the method for preparing a compound of formula I comprises: (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the fourth reaction mixture to precipitate the compound of Formula I.

[0142] In some embodiments, the method for preparing a compound of Formula I from a compound of Formula IIb-2 comprises: (a) a compound of formula IIb-2: [ka] , triethylamine, ethyl acetate, and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a ratio of about 1.0 relative to the compound of Formula IIb-2; (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the fourth reaction mixture to precipitate the compound of Formula I in at least 75% yield and at least 98% purity.

[0143] Compounds of formula I can be prepared with any acceptable amount of formula X-5 below. [ka] For example, a compound of formula I may be prepared to contain less than 5% (w / w), or less than 4, 3, 2, 1, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1% (w / w) of a compound of formula X-5. In some embodiments, a compound of formula I may be prepared to contain less than 1% (w / w) of a compound of formula X-5: [ka] In some embodiments, the compound of Formula I may be prepared to contain less than 0.75% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I may be prepared to contain less than 0.5% (w / w) of the compound of Formula X-5. In some embodiments, the compound of Formula I may be prepared to contain less than 0.2% (w / w) of the compound of Formula X-5.

[0144] In some embodiments, the compound of formula Ia contains less than 1% (w / w) of the compound of formula X-5a: [ka]

[0145] B. Preparation of Formula IIb-2 from Formula IIa The compound of formula IIb-2 can be prepared from the compound of formula IIa. In some embodiments, the present invention provides a compound of formula IIb-2: [ka] 1. A method for preparing (b) a compound of formula IIa: [ka] and sulfonic acids of the formula: [ka] forming a fifth reaction mixture comprising: During the ceremony, R 1 is C 1~6 Alkyl, C 1~10 haloalkyl, phenyl, or 4-methylphenyl; The subscript n is 1 to 4.

[0146] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of Formula IIb-2 can have the following structure: [ka]

[0147] The fifth reaction mixture can include any suitable solvent. In some embodiments, the fifth reaction mixture includes a fifth solvent. The fifth solvent can include, but is not limited to, pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, and chloroform. In some embodiments, the fifth solvent includes acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, ethanol, diethyl ether, methyl t-butyl ether (MTBE), toluene, or a combination thereof. In some embodiments, the fifth reaction mixture includes acetonitrile.

[0148] C. Preparation of Formula IIa from Formula III The compound of formula IIa can be prepared by a variety of methods. In some embodiments, the compound of formula IIa is (c) a Grignard reagent, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of 2.8 to 3.2 relative to the compound of formula III, and the Grignard reagent is present in a molar ratio of 2.8 to 3.3 relative to the compound of formula III, thereby preparing the compound of formula IIa.

[0149] The Grignard reagent can be any suitable Grignard reagent. In some embodiments, the Grignard reagent comprises iPrMgCl or iPrMgBr. In some embodiments, the Grignard reagent comprises iPrMgCl.

[0150] The Grignard reagent can be present in any suitable molar ratio relative to the compound of Formula III. For example, the Grignard reagent can be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.3, 2.8 to 3.2, 2.9 to 3.2, or 2.9 to 3.1 relative to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.8 to 3.3 relative to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.9 to 3.2 relative to the compound of Formula III. The Grignard reagent can be present in a molar ratio of about 2.90, or about 2.95, 3.00, 3.05, 3.10, 3.15, or about 3.20 relative to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 3.05 relative to the compound of formula III.

[0151] The pyridine may be present in any suitable ratio relative to the compound of Formula III. For example, the pyridine may be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.2, or 2.9 to 3.1 relative to the compound of Formula III. In some embodiments, the pyridine may be present in a molar ratio of 2.8 to 3.2 relative to the compound of Formula III. The pyridine may be present in a molar ratio of about 2.5, or about 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5 relative to the compound of Formula III. In some embodiments, the pyridine may be present in a molar ratio of about 3.0 relative to the compound of Formula III.

[0152] The sixth reaction mixture may also include a sixth solvent. The sixth solvent may be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or a combination thereof. In some embodiments, the sixth reaction mixture further includes a sixth solvent. In some embodiments, the sixth solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or a combination thereof. In some embodiments, the sixth reaction mixture further includes 2-methyltetrahydrofuran and toluene.

[0153] In some embodiments, the method of preparing the compound of Formula IIa also includes (c1) adding an acid and water to the sixth reaction mixture to form a work-up mixture, and (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa.

[0154] The acid in step (c1) can be any suitable acid. In some embodiments, the acid comprises formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or a mixture thereof. In some embodiments, the acid comprises acetic acid.

[0155] In some embodiments, the sixth reaction mixture further comprises an intermediate mixture comprising a compound of Formula IIa.

[0156] In some embodiments, the method for preparing a compound of formula IIb-2 comprises: (c) tetrahydrofuran, toluene, iPrMgCl, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of 3.05 relative to the compound of formula III; (c1) adding acetic acid and water to the sixth reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of formula IIa: [ka] (b) an intermediate mixture; forming a fifth reaction mixture comprising acetonitrile, and methanesulfonic acid to form a compound of formula IIb-2: [ka]

[0157] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (c) tetrahydrofuran, toluene, iPrMgCl, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of 3.05 relative to the compound of formula III; (c1) adding acetic acid and water to the sixth reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of formula IIa: [ka] (b) an intermediate mixture; forming a fifth reaction mixture comprising acetonitrile, and methanesulfonic acid to form a compound of formula IIb-2: [ka] (a) A compound of formula IIb-2, triethylamine, ethyl acetate, and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2; (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the reaction mixture to precipitate the compound of formula I in at least 75% yield and at least 98% purity.

[0158] In some embodiments, the present invention provides a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: (c) tetrahydrofuran, toluene, iPrMgCl, a compound of formula III: [ka] and 2-bromo-4-(trifluoromethyl)pyridine, [ka] wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of about 3.05 relative to the compound of formula III; (c1) adding acetic acid and water to the sixth reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of formula IIa: [ka] (b) an intermediate mixture; forming a fifth reaction mixture comprising acetonitrile, and methanesulfonic acid to form a compound of formula IIb-2: [ka] (a) A compound of formula IIb-2, triethylamine, ethyl acetate, and the following 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: [ka] wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2; (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the reaction mixture to precipitate the compound of Formula Ia in at least 75% yield and at least 98% purity.

[0159] VI. Low impurity composition The present invention provides compositions of Formula I that have low impurity content. In some embodiments, the present invention provides compositions of Formula I that have low impurity content. in an amount of at least 99% (w / w) of a compound of formula I: [ka] and one or more impurities in an amount of 0.01 to 1% (w / w).

[0160] The compositions of Formula I may contain one or more impurities present in a total amount of 0.01 to 1% (w / w). In some embodiments, the impurities are: a compound of formula X-4 in an amount of less than 0.5% (w / w) [ka] a compound of formula X-5 in an amount of less than 0.2% (w / w) [ka] and less than 0.1% (w / w) of a compound of formula X-6: [ka] It includes at least one of the following.

[0161] Impurities present in a composition of a compound of Formula I may include a compound of Formula X-4 in an amount of less than 1% (w / w). For example, a composition of a compound of Formula I may contain less than 1.0 (w / w), or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or less than 0.1% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.5% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.3% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% (w / w) of a compound of Formula X-4.

[0162] Impurities present in a composition of a compound of Formula I may include less than 1% (w / w) of the compound of Formula X-5. For example, a composition comprising a compound of Formula I may contain less than 1.0 (w / w), or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or less than 0.1% (w / w) of the compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 1% (w / w) of the compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.75% (w / w) of the compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.5% (w / w) of the compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.2% (w / w) of the compound of Formula X-5.

[0163] Impurities present in a composition comprising a compound of Formula I may contain less than 1.0 (w / w), or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or less than 0.1% (w / w) of the compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.25% (w / w) of the compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.2% (w / w) of the compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% (w / w) of the compound of Formula X-6.

[0164] In some embodiments, the impurities include the compound of formula X-4 in an amount of less than 0.1% (w / w), the compound of formula X-5 in an amount of less than 0.15% (w / w), and the compound of formula X-6 in an amount of less than 0.1% (w / w).

[0165] Impurities present in compositions containing compounds of formula I include the following: methyl 1-methyl-1H-pyrazole-4-sulfonate; [ka] In some embodiments, a composition comprising a compound of Formula I may contain the impurity methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 10 ppm. For example, a composition comprising a compound of Formula I may contain the impurity methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 10 ppm, or less than 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, a composition comprising a compound of Formula I may contain the impurity methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 8 ppm. In some embodiments, a composition comprising a compound of Formula I may contain the impurity methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 6 ppm. In some embodiments, a composition comprising a compound of Formula I may contain the impurity methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm.

[0166] Impurities present in compositions containing compounds of formula I include the following: 1-methyl-1H-pyrazole-4-sulfonyl chloride, [ka] In some embodiments, a composition comprising a compound of Formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 10 ppm. For example, a composition comprising a compound of Formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 10 ppm, or less than 9, 8, 7, 6, 5, or less than 4 ppm. In some embodiments, a composition comprising a compound of Formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 8 ppm. In some embodiments, a composition comprising a compound of Formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 6 ppm. In some embodiments, a composition comprising a compound of Formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm.

[0167] In some embodiments, the impurities further comprise 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm, and methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm. In some embodiments, the impurities further comprise 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm, methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm, ethyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm, and isopropyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm.

[0168] Compositions containing compounds of Formula I may also contain one or more of the following impurities: A compound having the following formula XD in an amount of less than 0.40% (w / w): [ka] A compound having the following formula XE in an amount of less than 0.40% (w / w): [ka] and a compound having the following formula XF in an amount of less than 0.30% (w / w). [ka]

[0169] In some embodiments, compositions comprising a compound of Formula I may also contain one or more of the following impurities: A compound having the following formula XD in an amount of less than 0.40% (w / w): [ka] and a compound having the following formula XE in an amount of less than 0.40% (w / w). [ka]

[0170] In some embodiments, a composition comprising a compound of formula I may contain an amount of less than 0.30% (w / w) of a compound having the following formula XF: [ka]

[0171] In some embodiments, the present invention provides a method for treating a cancer cell comprising: in an amount of at least 99% (w / w) of a compound of formula Ia: [ka] and one or more impurities in an amount of 0.01 to 1% (w / w).

[0172] In some embodiments, the impurity is a compound of formula X-4a in an amount of less than 0.5% (w / w): [ka] a compound of formula X-5a in an amount of less than 0.2% (w / w): [ka] and less than 0.1% (w / w) of a compound of formula X-6a: [ka] It includes at least one of the following.

[0173] In some embodiments, the impurities include the compound of formula X-4a in an amount of less than 0.1% (w / w), the compound of formula X-5a in an amount of less than 0.15% (w / w), and the compound of formula X-6a in an amount of less than 0.1% (w / w).

[0174] In some embodiments, the impurities further comprise one or more of 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride in an amount less than 4 ppm, methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm, ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm, and isopropyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm. In some embodiments, the impurities further include 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride in an amount less than 4 ppm, methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm, ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm, and isopropyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in an amount less than 4 ppm.

[0175] In some embodiments, the impurity is a compound of formula X-Da in an amount of less than 0.40% (w / w): [ka] and a compound of formula X-Ea in an amount of less than 0.40% (w / w): [ka] Further includes:

[0176] VII. Crystalline Form of Formula IIb The present invention also provides a compound of formula IIb in crystalline form. A. (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate

[0177] In some embodiments, the present invention provides the following (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate salt in a crystalline form: [ka] It is characterized by an X-ray powder diffraction (XRPD) pattern with peaks at about 18.2°, 18.3°, and 19.7° 2-θ±0.2° 2-θ.

[0178] In some embodiments, the XRPD further comprises peaks at about 9.9°, 16.5°, and 17.6° 2-θ ± 0.2° 2-θ. In some embodiments, the XRPD further comprises peaks at about 5.0°, 14.5°, 17.9°, 19.0°, 20.8°, 22.9°, 23.4°, and 25.3° 2-θ ± 0.2° 2-θ. In some embodiments, the XRPD further comprises peaks at about 5.0°, 9.9°, 14.5°, 16.5°, 17.6°, 17.9°, 18.2°, 18.3°, 19.0°, 19.7°, 20.8°, 22.9°, 23.4°, and 25.3° 2-θ ± 0.2° 2-θ. In some embodiments, the crystalline form is characterized by an XRPD pattern substantially as depicted in FIG.

[0179] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset at about 167° C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as depicted in FIG.

[0180] B. (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone oxalate In some embodiments, the present invention provides the following (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone oxalate in a crystalline form: [ka] It is characterized by a powder X-ray diffraction (XRPD) pattern with peaks at approximately 6.1, 8.4, 10.6, and 15.6 degrees 2-θ ± 0.2 degrees 2-θ.

[0181] In some embodiments, the XRPD further comprises peaks at about 12.3, 13.0, and 25.3 degrees 2-θ ± 0.2 degrees 2-θ. In some embodiments, the XRPD further comprises peaks at about 16.2, 17.1, 18.2, 19.9, 21.7, 22.9, 23.7, and 24.6 degrees 2-θ ± 0.2 degrees 2-θ. In some embodiments, the XRPD further comprises peaks at about 6.1, 8.4, 10.6, 12.3, 13.0, 15.6, 16.2, 17.1, 18.2, 19.9, 21.7, 22.9, 23.7, 24.6, and 25.3 degrees 2-θ ± 0.2 degrees 2-θ. In some embodiments, the crystalline form is characterized by a powder X-ray diffraction (XRPD) pattern substantially as depicted in FIG. 5.

[0182] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset at about 168° C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as depicted in FIG.

[0183] C. (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone Hydrochloride In some embodiments, the present invention provides the following (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrochloride salt in a crystalline form: [ka] It is characterized by a powder X-ray diffraction (XRPD) pattern with peaks at approximately 15.3, 22.0, 23.1, and 24.5° 2-θ ± 0.2° 2-θ.

[0184] In some embodiments, the XRPD further comprises peaks at about 7.0, 13.5, 14.8, 17.7, 18.3, 19.2, 23.5, and 25.2 degrees 2-theta ± 0.2 degrees 2-theta, hi some embodiments, the XRPD further comprises peaks at about 8.1, 11.5, 21.2, 26.9, 27.2, 28.1, 30.1, and 32.4 degrees 2-theta ± 0.2 degrees 2-theta. In some embodiments, the XRPD comprises peaks at about 7.0, 8.1, 11.5, 13.5, 14.8, 15.3, 17.7, 18.3, 19.2, 21.2, 22.0, 23.1, 23.5, 24.5, 25.2, 26.9, 27.2, 28.1, 30.1, and 32.4 degrees 2-theta ± 0.2 degrees 2-theta. In some embodiments, the crystalline form is characterized by a powder X-ray diffraction (XRPD) pattern substantially as depicted in FIG. 8.

[0185] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset at about 215° C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as shown in FIG.

[0186] VIII. Composition In some embodiments, the present invention provides pharmaceutical compositions comprising the low-impurity compositions of the present invention and a pharmaceutically acceptable excipient.

[0187] The low-impurity compositions of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. The low-impurity compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compounds described herein can also be administered by inhalant, for example, intranasally. Additionally, the low-impurity compositions of the present invention can be administered transdermally. The compounds of formula I of the present invention can also be administered by intraocular, intravaginal, and rectal routes, including suppositories, insufflation, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Thus, the present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and / or excipients and a compound of formula I.

[0188] For preparing pharmaceutical compositions from the low-impurity compositions of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details regarding formulation and administration techniques are well-documented in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0189] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties and, optionally, additional excipients in suitable proportions and compacted in the shape and size desired.

[0190] Powders, capsules, and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other excipients, is surrounded by the carrier and thus bound to it. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0191] Suitable solid excipients include, but are not limited to, carbohydrate or protein fillers, such as sugars such as lactose, sucrose, mannitol, or sorbitol, starches derived from corn, wheat, rice, potato, or other plants, celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose, and gums such as gum acacia and tragacanth, and proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0192] The dragee cores are provided with a suitable coating, such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions, which may also contain suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally, for example, in push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerin or sorbitol. Push-fit capsules may contain the compound of Formula I mixed with a filler or binder, such as lactose or starch, a lubricant, such as talc or magnesium stearate, and, optionally, a stabilizer. In soft capsules, the compound of Formula I may be dissolved or suspended in a suitable liquid, such as fatty acid, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0193] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0194] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0195] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration immediately before use.These liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to active ingredients, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

[0196] In oily suspensions, the compound of Formula I can be prepared by suspending it in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils, such as liquid paraffin, or a mixture thereof. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners can be added to provide a palatable oral preparation, such as glycerin, sorbitol, or sucrose. These preparations can be preserved by adding antioxidants, such as ascorbic acid. For examples of oily vehicles for injection, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be the above-mentioned vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifiers include natural gums, such as gum acacia and gum tragacanth; natural phosphatides, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents, as in the preparation of syrups and elixirs. Such preparations may also contain demulcents, preservatives, or coloring agents.

[0197] The compounds of formula I of the present invention can be delivered transdermally, topically, and formulated as spreader sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0198] The compound of formula I and the composition of the present invention can also be delivered as microspheres for sustained release in the body.For example, microspheres can be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J.Biomater Sci.Polym.Ed.7:623-645,1995), or as biodegradable and injectable gel formulations (see, for example, Gao Pharm.Res.12:857-863,1995), or as microspheres for oral administration (see, for example, Eyles, J.Pharm.Pharmacol.49:669-674,1997).Both transdermal and intradermal routes provide constant delivery over weeks or months.

[0199] In some embodiments, the formulation of the compound of Formula I of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by binding to liposomes that bind to cell surface membrane protein receptors that cause endocytosis, or by using ligands that directly bind to oligonucleotides.The use of liposomes can focus the delivery of GR modulators to target cells in vivo, especially when the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a specific organ. (See, for example, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989).

[0200] Pharmaceutical preparations are preferably in unit dosage form. In this dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a packaged preparation, for example, a package containing individual amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0201] The amount of active ingredient in a unit dose preparation can vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. For example, doses can be 50 mg, or 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. The composition can also contain other compatible therapeutic agents, if desired.

[0202] Dosage regimens also take into account pharmacokinetic parameters well known in the art, i.e., rates of absorption, bioavailability, metabolism, clearance, etc. (See, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; Remington, supra, most recently). The current state of the art allows the clinician to determine the dosing regimen for the individual patient, the GR and / or MR modulator, and the disease or condition being treated.

[0203] Single or multiple administrations of a formulation of a compound of Formula I can be administered depending on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the condition. Thus, in one embodiment, a pharmaceutical formulation for oral administration of a compound of Formula I is administered in a daily amount of about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, the dosage is about 1 mg to about 20 mg per kg of body weight per patient per day. Lower dosages may be used, particularly when the agent is administered to an anatomically isolated site, such as the cerebrospinal fluid (CSF) space, as opposed to orally, into the bloodstream, a body cavity, or the lumen of an organ. Substantially higher dosages may be used for local administration. Actual methods for preparing formulations containing a compound of Formula I for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington, cited above. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0204] The compounds described herein can be used in combination with each other, with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0205] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by combined formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuncts may be linked or conjugated to each other.

[0206] After the pharmaceutical compositions containing the compounds of Formula I of the present invention have been formulated in one or more acceptable carriers, they can be placed in an appropriate container and labeled for treatment of a designated condition. For administration of the compounds of Formula I, such labeling would include instructions regarding, for example, the amount, frequency and method of administration.

[0207] In some embodiments, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a cavity or lumen of an organ. Administration formulations typically comprise a solution of the compositions of the present invention dissolved in one or more pharmaceutically acceptable carriers. Additionally, sterile, fixed oils can be conventionally employed as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can similarly be used in the preparation of injectable solutions. These solutions are sterile and generally free of undesirable material. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the compositions of the present invention in these formulations can vary widely and will be selected primarily based on fluid volume, viscosity, body weight, etc., depending on the particular method of administration selected and the patient's needs. For intravenous (IV) administration, the preparation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0208] In some embodiments, formulations of the compositions of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by binding to liposomes that bind to cell surface membrane protein receptors that cause endocytosis, or by using ligands that bind directly to oligonucleotides.The use of liposomes can target the delivery of the compositions of the present invention to target cells in vivo, especially when the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a specific organ. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0209] IX. Methods and Uses In some embodiments, the present invention provides a method for treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of any one of the low-impurity compositions of the present invention or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0210] In some embodiments, the present invention provides a method for treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment an effective amount of any one of the low-impurity compositions of the present invention or a pharmaceutical composition of the present invention.

[0211] In some embodiments, the disorder or condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by excess cortisol associated with adrenal gland disease, addiction, psychosis, eating disorders, cachexia, post-traumatic stress syndrome, post-operative fractures, GR-related metabolic disorders, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and neurological disorders in premature infants.

[0212] In some embodiments, the methods include administering one or more second agents (e.g., therapeutic agents). In some embodiments, the methods include administering a therapeutically effective amount of one or more second agents (e.g., therapeutic agents). In some embodiments, the second agents are agents known to be useful in modulating the glucocorticoid receptor. In some embodiments, the second agent is for treating amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by excess cortisol associated with adrenal gland disease, addiction, psychosis, eating disorders, cachexia, post-traumatic stress syndrome, post-operative fractures, GR-related metabolic disorders, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and neurological disorders in premature infants. In some embodiments, the second agent is for treating major psychotic depression, stress disorders, or antipsychotic-induced weight gain. In some embodiments, the second agent is an agent for treating non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the second agent is an agent for treating an addictive disorder. In some embodiments, the second agent is an agent for treating cancer. In some embodiments, the second agent is an anti-cancer agent. In some embodiments, the second agent is a chemotherapy.

[0213] In some embodiments, any one of the low-impurity compositions of the present invention, or a pharmaceutical composition of the present invention, can be used in a method for treating a disorder or condition by modulating the glucocorticoid receptor.

[0214] In some embodiments, any one of the low-impurity compositions of the present invention, or a pharmaceutical composition of the present invention, can be used in a method for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0215] In some embodiments, any one of the low-impurity compositions of the present invention, or a pharmaceutical composition of the present invention, can be used in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0216] In some embodiments, any one of the low-impurity compositions of the present invention, or a pharmaceutical composition of the present invention, can be used in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor. [Example]

[0217] X. Working Example In the methods that follow, the following abbreviations are used: [Table 1]

[0218] Powder X-ray diffraction (XRPD). XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed by transmission and held between low-density polyethylene films. The XRPD program used included the following parameters: (1) 2θ range of 3–40°, (2) step size of 0.013°, (3) count time of 99 s, and (4) a run time of approximately 22 min. XRPD patterns were screened using HighScore Plus 2.2c software.

[0219] Differential Scanning Calorimetry (DSC). DSC analyses were performed on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminum pans. Each sample was heated at a rate of 10°C / min under nitrogen up to 300°C. Indium metal was used as the calibration standard. Temperatures were reported at the time of transition, rounded to two decimal places (0.01°C).

[0220] The reaction step of the present invention can be carried out for any suitable reaction time. For example, the reaction time can be minutes, hours, or days. In some embodiments, the reaction time can be several hours, such as at least 8 hours. In some embodiments, the reaction time can be several hours, such as at least overnight. In some embodiments, the reaction time can be several days. In some embodiments, the reaction time can be at least two hours. In some embodiments, the reaction time can be at least eight hours. In some embodiments, the reaction time can be at least several days. In some embodiments, the reaction time can be about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 10 hours, or about 12 hours, or about 14 hours, or about 16 hours, or about 18 hours, or about 20 hours, or about 22 hours, or about 24 hours. In some embodiments, the reaction time can be about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or about 1 week or more.

[0221] The reaction steps of the present invention can be carried out at any suitable reaction temperature. Typical temperatures include, but are not limited to, below room temperature, room temperature, or above room temperature. Other temperatures useful in the methods of the present invention include about -40°C to about 65°C, or about room temperature to about 40°C, or about 40°C to about 65°C, or about 40°C to about 60°C. In some embodiments, the reaction mixture can be at a temperature of about room temperature, or about 15°C, or about 20°C, or about 25°C, or about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C.

[0222] Example 1. Preparation of tert-butyl (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylate [ka] 0.7-0.8 parts 2-bromo-4-(trifluoromethyl)pyridine is added to 6.8 parts toluene. The solution is cooled to -5 to 5°C under nitrogen. 1.3-1.5 parts of the reagent, i-propylmagnesium bromide (3.0 M solution in 2-Me-THF), is added to the solution while maintaining the batch temperature at -5 to 5°C. The Grignard reaction occurs at -5 to 5°C over ≥6 hours until completion (≤15% 2-bromo-4-(trifluoromethyl)pyridine by HPLC).

[0223] A solution of 1.0 parts of (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate 6-(tert-butyl) 4a-methyl (Compound 9) in 7.0 parts of toluene is added while maintaining the batch temperature at −5 to 5° C. The reaction mixture is allowed to warm to 15 to 25° C. and maintained at this temperature for at least 12 hours until the coupling reaction is complete (≦1.0% of Compound 9 remaining by HPLC).

[0224] The reaction is quenched by the addition of 0.28 parts acetic acid in 10 parts water. The solution is stirred and then allowed to settle. The aqueous phase is discarded, and the organic phase is washed with 12 parts aqueous hydrochloric acid. The aqueous phase is discarded, and the organic phase is washed with 12 parts water. The aqueous phase is discarded. The product is dried by azeotropic distillation at ≦50°C (≦0.1% water by KF; ≦20 ppm 2-MeTHF by HPLC). The product is isolated in toluene (5-8% w / w) to give 1.1-1.3 parts (90-100% molar yield). Characterization data for the title compound was consistent with that of Intermediate 29 in U.S. Pat. No. 8,859,774.

[0225] Example 2. Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Relacorilant) Method I [ka] The target compound was prepared using the following steps. Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrobromide [ka]

[0226] A solution of 1.0 parts of the product from Example 1 in toluene is added to a vessel. 1.0 to 1.2 parts of hydrogen bromide gas is added at a temperature of -5 to 5°C until the reaction is complete (≤1.0% of the product from Example 1 remains by HPLC). The mixture is transferred to a filter dryer and washed with at least 2.6 parts of toluene at a temperature of -5 to 5°C.

[0227] The solid is dried under vacuum / nitrogen at -5 to 10°C for at least 24 hours, sampling every 12 to 24 hours (≤25% toluene remaining by GC). The tris-hydrobromide compound is isolated in 1.1 to 1.3 parts (85 to 100% molar yield). Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

[0228] Add 1.0 parts of the tris-hydrobromide intermediate from Step 2 to 7.8 parts isopropyl acetate at -5 to 5°C. Add 0.3 parts pyrazole sulfonyl chloride and 1.2 parts triethylamine, and continue stirring for a minimum of 3 hours until the reaction is complete (≤2% tris-hydrobromide intermediate remaining by HPLC). The organic solution is washed with at least 8.8 parts water at 15 to 25°C. The organic phase is then washed with 3.7 parts HCl / water solution (adjusted to pH 4-5). The organic phase is then washed with 13 parts NaCl / water solution (adjusted to pH 5-6).

[0229] To the organic solution, 0.3 parts silica gel is added. The solution is filtered and rinsed with at least 1.2 parts isopropyl acetate. The mother liquor is concentrated under vacuum at ≦50°C and solvent exchanged with acetone (≦10% isopropyl acetate by GC). The crude relacorilant is isolated in acetone (target 40% w / w) to give 0.6-0.8 parts (70-90% molar yield) of crude relacorilant. Characterization data for the crude relacorilant was consistent with that of Example 18 of U.S. Pat. No. 8,859,774.

[0230] Example 3. Purification of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone The product of Example 2 was purified by the following method.

[0231] Purification by preparative HPLC The HPLC column was pressure-packed with C18 using isopropyl alcohol. Because this chromatographic resin was dedicated to the production of relacorilant, the packed column was reused for multiple cycles within each product lot. A usage test was performed to determine the collection time required to collect product fractions within the elution parameters shown in Table 2.

[0232] The packed column was equilibrated with 1–2 column volumes of mobile phase A. Crude relacorilant (1.0–1.5 kg) in solution was loaded onto the chromatographic column at a flow rate of 3 L / min. The product was eluted from the column using a gradient from mobile phase B to mobile phase C over 100 min at a flow rate of 4.5 L / min. Fractionation was performed by splitting the column eluate into multiple collection tanks according to established collection times in the in-service test. After column collection, the column was washed with buffer C at a flow rate of 6.5 L / min for 10 min to regenerate the packing material.

[0233] The column equilibration, loading, elution, fraction collection, and column washing were then repeated to obtain additional fractions. The eluted fractions in the collection vessel were sampled and tested for relacorilant purity and related substances. Eluted fractions that met the in-process acceptance criteria (≥98.0% purity, ≤0.6% Formula X-5, ≤0.20% individual impurities by HPLC) were identified as product fractions and pooled. [Table 2] [Table 3]

[0234] Purification with MTBE / heptane After preparative HPLC purification, the pool of relacorilant fractions is further purified as described in the following steps. A solution of relacorilant in ACN:FA:water is saturated with sodium chloride and extracted with a total of ≥45 parts ethyl acetate. The ethyl acetate solution is washed with ≥30 parts NaCl / water. The organic phase is concentrated under vacuum at ≤50°C to a concentration of 3-5 parts relacorilant in ethyl acetate (≤1% by KF). A solvent exchange is performed with MTBE and concentrated under vacuum at ≤50°C to ≥11 parts by volume of relacorilant in MTBE solution (≤5% ethyl acetate by GC). The relacorilant solution is filtered through a CUNO cartridge filter (≤0.30 Formula X-5, ≤0.20 Formula X-6, ≤0.15 Formula X-4, ≤0.10% unknown impurity by HPLC).

[0235] The relacorilant in MTBE solution is slowly added to 10 parts heptane at 30-40°C, and the solution is cooled to -5-5°C to precipitate the relacorilant. The relacorilant precipitate is collected and washed with ≥2 parts heptane. The wet filter cake is dried at ≤50°C for ≥4 hours (GC: ≤15% MTBE, ≤15% heptane, ≤4 ppm methyl bromide, ≤4 ppm 2-bromopropane, ≤4 ppm 1,4-dibromopentane). The purified relacorilant is isolated to yield 0.60-0.90 parts (60-90% molar yield) of purified relacorilant.

[0236] Washing with methanol solvent The purified relacorilant was dissolved in 13.6 parts methanol. The methanol solution was concentrated under vacuum at ≦50° C. to ≧9 parts by volume of a solution of relacorilant in MTBE (≦300 ppm MTBE, ≦300 ppm heptane by GC). This solution was slowly added to 15 parts water through a 0.22 μm in-line filter to precipitate the relacorilant. The relacorilant precipitate was collected by filtration and washed with at least 5 parts water (≦4 ppm 1-methyl-1H-pyrazole-4-sulfonyl chloride, ≦4 ppm methyl 1-methyl-1H-pyrazole-4-sulfonate, ≦4 ppm ethyl 1-methyl-1H-pyrazole-4-sulfonate, ≦4 ppm isopropyl 1-methyl-1H-pyrazole-4-sulfonate, ≦50 ppm formic acid by HPLC). The relacorilant was then dried under vacuum (KF, ≦1.1%; GC, ≦4500 ppm isopropyl acetate, ≦4500 ppm acetone, ≦370 ppm acetonitrile, ≦4500 ppm ethyl acetate, ≦2700 ppm methanol, ≦5000 ppm heptane, ≦5000 ppm MTBE).

[0237] Example 4. Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Relacorilant) Method II [ka] The target compound was prepared using the following steps. Step 1. Preparation of (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylate tert-butyl ester [ka]

[0238] Step 1 involves the addition of 2-bromo-4-(trifluoromethyl)pyridine (3.0 equivalents) to (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate 6-(tert-butyl) 4a-methyl (Compound 9, 1.0 equivalents), facilitated by halo-metal exchange using the Grignard reagent iPrMgCl (3.05 equivalents). During workup, the intermediate hemiketal is converted to a ketone, and the product of Step 1 is isolated as a solution in toluene and used directly in the next step. 1. Inert the reactor with nitrogen by purging with vacuum. 2. Using the residual vacuum, charge toluene (40.0 Kg) into the reactor through the solvent addition line. 3. Stir the reactor contents vigorously for at least 5 minutes. 4. Drain the reactor contents through the bottom outlet valve into a suitable waste receptacle. 5. Set up the reactor for distillation and apply full vacuum. Ensure the reactor is apparently dry. 6. (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate 6-(tert-butyl)4a-methyl (Compound 9, 7.2 Kg) is charged to the reactor via the manway. 7. Inert the reactor with nitrogen. 8. Using the residual vacuum, charge toluene (31.2 Kg) into the reactor through the solvent addition line and begin agitation. 9. Stir the contents of the reactor at 25° C. for at least 5 minutes to dissolve compound 9. 10. Stop the agitation and transfer the contents of the reactor to a clean, plastic-coated drum of known weight. 11. Using the residual vacuum, charge toluene (6.2 Kg) into the reactor through the solvent addition line. 12. Stir the contents of the reactor for at least 5 minutes. 13. Stop the agitation and transfer the contents of the reactor to the plastic drum used in step 10. 14. Using residual vacuum, charge toluene (40.0 Kg) into the reactor through the solvent addition line. 15. Stir the contents of the reactor for at least 2 minutes. 16. Stop the agitation and drain the reactor contents through the bottom outlet valve into a disposal drum. 17. Using the residual vacuum, charge toluene (100 Kg) into the reactor through the solvent addition line. 18. Pressure purge the reactor with nitrogen three times. 19. 2-Bromo-4-(trifluoromethyl)pyridine (11.56 Kg) is charged under vacuum through the reagent addition line. 20. Cool the reactor contents to 0°C. 21. Dose approximately 20% isopropylmagnesium chloride in THF (26.4 Kg) into the reactor through the reagent addition line over a period of at least 20 minutes, maintaining the batch temperature below 5°C. 22. Age the reactor contents at 0°C for at least 2 hours. 23. Sample the reactor to determine the conversion of 2-bromo-4-(trifluoromethyl)pyridine to Des-bromo (89% conversion was achieved as determined at 254 nm). 24. Dump the contents of the plastic-coated drum from steps 10 and 13 containing the toluene solution of compound 9 into the reactor through the reagent addition line over a period of at least 20 minutes, maintaining the batch temperature below 5°C. 25. Warm the reactor contents to 20°C. 26. Age the reactor contents at 20°C for at least 1 hour. 27. Sample the reactor to determine reaction conversion of compound 9 to the product of Step 1 (at 210 nm, 100% conversion was achieved). 28. Cool the reactor contents to 0°C. 29. Dose acetic acid (5.06 Kg) into the reactor through the solvent addition line over a period of at least 20 minutes. Ensure the batch temperature remains below 10°C during the addition. 30. Warm the reactor contents to 20°C. 31. Sample the reactor to determine the reaction profile and LCAP of the product of Step 1 (detected at 210 nm as 82.2%). 32. Age the reactor contents at 22°C for a minimum of 12 hours. 33. Add purified water (132.2 Kg) to a clean looking drum and add 37% hydrochloric acid (14.2 Kg) to make a 1M hydrochloric acid solution. 34. Using the remaining vacuum, charge half of the contents of a drum of 1M hydrochloric acid (73.2 Kg) into the reactor through the solvent addition line. 35. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 36. Drain the lower aqueous layer into a clean drum of known mass. 37. Using the remaining vacuum, charge the remainder of the contents of 1M hydrochloric acid (73.2 Kg) into the reactor through the solvent addition line. 38. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 39. Drain the lower aqueous layer into a clean drum of known mass. 40. Sodium bicarbonate (1.3 Kg) is charged to a 75 L drum, then purified water (42.7 Kg) is charged to the drum and mixed until dissolved to produce a 3 wt% sodium bicarbonate solution. 41. Using the residual vacuum, charge the contents of a drum containing 3 wt % sodium bicarbonate solution (44.0 Kg) through the solvent addition line into the reactor. 42. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 43. Drain the lower aqueous layer into a clean drum of known mass. 44.Pour purified water (100 kg) into a clean-looking drum. 45. Using the residual vacuum, charge the purified water (72 Kg) from step 44 into the reactor through the solvent addition line. 46. Stir the reactor contents for at least 15 minutes, then stop stirring and allow the two-phase mixture to settle. 47. Drain the lower aqueous layer into a clean drum of known mass. 48. Construct a reactor for distillation. 49. Distill the reactor contents under reduced pressure, maintaining the temperature below 45°C, to achieve a final volume of approximately 72 L. 50. Cool the reactor contents to 20°C. 51. Transfer the organic layer from the reactor through a 10 μm cartridge filter into a clean looking blue HDPE (high density polyethylene) coated drum. 52. Take a sample from this drum and determine the weight percent of both based on the product from Step 1 and the HPLC reaction profile (the determined weight percent is 13.99%). 53. The recovery rate was determined to be 99.54%.

[0239] The characterization data for the title compound was consistent with that of Intermediate 29 in US Pat. No. 8,859,774. Step 2. Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-methanesulfonate [ka]

[0240] Step 2 involves Boc deprotection achieved using methanesulfonic acid (4.5 equiv.) followed by isolation of the product as the TrisMSA salt by crystallization from the reaction mixture initiated using 0.25 mol % of the Step 2 TrisMSA salt seed. 1. Inert the reactor with nitrogen by purging with vacuum. 2. Using the residual vacuum, charge the solution of the product of Step 1 (70 Kg, corrected to 8.90 Kg) from the solvent addition line through the in-line filter into the reactor and begin agitation. 3. Inert the reactor by partial vacuum purging (-300 to -400 mbar). 4. Distill the reactor contents under reduced pressure, maintaining the temperature below 40° C., to achieve a final volume of approximately 18 L. 5. Using the residual vacuum, charge acetonitrile (71 Kg) into the reactor through the solvent addition line. 6. Distill the reactor contents under reduced pressure, maintaining the temperature below 40° C., to achieve a final volume of approximately 18 L. 7. Using the residual vacuum, charge acetonitrile (14 Kg) into the reactor through the solvent addition line. 8. Cool the reactor contents to 22°C. 9. Remove the sample from the reactor. 1 The toluene content is confirmed by H NMR (result: 1.135 wt / wt). 10. Cool the reactor contents to 0°C. 11. Using residual vacuum, charge methanesulfonic acid (7.1 Kg) into the reactor through the reagent addition line (over at least 15 minutes), maintaining the batch temperature below 10°C. 12. Using the residual vacuum, charge acetonitrile (2 Kg) into the reactor through the reagent addition line. 13. Inert the reactor by partial vacuum purging (-300 to -400 mbar). 14. Slowly warm the reactor contents to 22°C over a period of at least 20 minutes. 15. Charge the reactor with seeds (30 g) of the product from step 2. 16. Age the reactor contents at 22°C for at least 3 hours. 17. Take a sample from the reactor and check the LCAP (Liquid Chromatography Area Percentage) of the free base of the product from Step 2 relative to the product from Step 1 (result: >99%). 18. Dose isopropyl acetate (39 Kg) into the reactor through the solvent addition line using the dosing pump over a minimum of 30 minutes. 19. Age the reactor contents at 22°C for at least 1 hour. 20. Remove a sample (approximately 30-50 mL) from the reactor. Filter the slurry and verify the concentration of free base of the product of Step 2 in the liquid by HPLC (result: 5.8 mg / mL). 21. Stop the agitation and drain the reactor contents into a pressure filter and collect the liquid in a plastic-lined drum. 22. Charge tetrahydrofuran (24 Kg) into the reactor through the solvent addition line using the dosing pump and begin stirring. 23. Stop the agitation and then drain the contents through the outlet valve at the bottom of the reactor into a pressure filter and collect the liquid in a plastic-lined drum. 24. Tetrahydrofuran (24 kg) is poured through a spray ball into a pressure filter and the liquid is collected in a plastic-lined drum. 25. Dewater the solids on a pressure filter under a stream of nitrogen. 26. Transfer the solids from the pressure filter into clean looking trays and place in a tray dryer. 27. Place the dryer under vacuum and set to minimum nitrogen flow. 28. Set the oven to 40°C and dry the solids for at least 18 hours. 29. Cool the dryer to 20°C and return to atmospheric pressure. 30. Transfer the solids from the dryer into clean, double-bagged, anti-static polyethylene liner bags of known weight with two desiccant pouches between the liner bags, and place the liner bags into an HDPE white keg. 31. The isolated yield is 9.6 Kg of Step 2 Tris MSA salt and 60.5 wt% of Step 2 free base, for a 79.1% yield. [Table 4-1] [Table 4-2]

[0241] Step 3. Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka] The TrisMSA salt from Step 2 in ethyl acetate is reacted with 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.0 equiv.) along with triethylamine (4.1 equiv.). Once the reaction is complete as determined by HPLC, excess sulfonyl chloride is removed by reaction with a scavenger (N-methylpiperazine, 0.25 equiv.). The reaction is then worked up by washing with 1 M HCl followed by water. A solvent exchange to methanol is performed, and the relacorilant precipitates as an amorphous solid upon slow addition to water at ambient temperature. 1. Inert the reactor with nitrogen. 2. Charge the product of Step 2 (Tris MSA salt) (0.779 Kg, corrected to 0.474 Kg (free base)) to the reactor. 3. Ethyl acetate (10.08 Kg) is charged into the reactor using a dosing pump and stirred. 4. Inert the reactor by partial vacuum purging (-300 to -400 mbar). 5. Cool the reactor contents to -5°C. 6. Using the dosing pump, dose (over at least 5 minutes) triethylamine (0.443 Kg) while maintaining the batch temperature at 5°C. 7. Age the reactor contents at -5°C for at least 5 minutes. 8. 1-Methyl-1H-pyrazole-4-sulfonyl chloride (0.198 Kg) is charged to a clean HDPE drum of known weight and ethyl acetate (2.012 Kg) is charged to the drum. 9. Mix the contents of the drum thoroughly to ensure complete dissolution. 10. Dump the contents of the drum into the reactor through the solvent addition line using the dosing pump (over at least 5 minutes), maintaining the batch temperature below 5°C. 11. Dose ethyl acetate (1.0 Kg) into the reactor via the dosing pump setup from step 10. 12. Warm the reactor contents to 20°C over at least 15 minutes. 13. Age the reactor contents at 20°C for at least 4 hours. 14. Remove a sample from the reactor and analyze using HPLC to confirm the LCAP of the relacorilant relative to Step 2 (free base). The result is 99.1% at 243 nm. 15. Using a dosing pump, charge N-methylpiperazine (26.7 g) to the reactor. 16. Age the reactor contents at 20°C for at least 14 hours. 17. A sample was taken from the reactor and analyzed by HPLC to determine the amount of 1-methyl-1H-pyrazole-4-sulfonyl chloride consumed. As a result, no sulfonyl chloride was detected. 18. Purified water (7.0 Kg) is added to a clean-looking 25 L black antistatic drum, followed by concentrated hydrochloric acid (0.77 Kg) to produce a 1.0 M HCl solution. 19. Charge 1.0 M HCl solution (3.93 Kg) into the reactor through the solvent addition line. 20. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 21. Drain the lower aqueous layer through the bottom outlet valve into a 200 L plastic-lined drum. 22. Charge 1.0 M HCl solution into the reactor through the solvent addition line (3.88 Kg). 23. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 24. Drain the lower aqueous layer through the bottom outlet valve into a 200 L plastic-lined drum. 25. Add purified water (3.92 kg) through the solvent addition line using the dosing pump and begin stirring. 26. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 27. Drain the lower aqueous layer through the bottom outlet valve into a 200 L plastic-lined drum. 28. Add purified water (3.91 kg) through the solvent addition line using the dosing pump and begin stirring. 29. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 30. Drain the lower aqueous layer through the bottom outlet valve into a 200 L plastic-lined drum. 31. Add purified water (3.92 kg) through the solvent addition line using the dosing pump and begin stirring. 32. Stir the contents of the reactor for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle. 33. Drain the lower aqueous layer through the bottom outlet valve into a 200 L plastic-lined drum. 34. Discharge the contents of the reactor into a clean 25 L drum of known mass (discharge mass, 12.31 kg). 35. Remove a sample from the drum and analyze it to determine the assay yield of relacorilant (Result: 644.30 g, 103.1%). 36. Assemble an in-line filter to connect the outlet of the Whatman filter to the rotary evaporator. 37. Using the residual vacuum, transfer the contents of the 25 L drum through a Whatman filter to a rotary evaporator. 38. Concentrate the relacorilant solution from step 37 to a final volume of approximately 1.5 L. 39. Methanol (6.16 kg) is added to a rotary evaporator. 40. Concentrate the relacorilant solution from step 39 to a final volume of approximately 3.0 L. 41. Take out the sample.1 Analyze the level of residual ethyl acetate by H NMR (result: 1.87% wt / wt ethyl acetate). 42. Transfer the relacorilant solution from step 40 into a clean 5 L shot bottle with a known mass. 43. Dose methanol (4.0 Kg) into the reactor through the solvent addition line using the dosing pump and stir for at least 5 minutes. 44. Transfer the contents of the reactor into a clean, plastic-coated drum labeled for waste. 45. Charge purified water (11.68 Kg) into the reactor through the solvent addition line using the dosing pump and begin agitation. 46. Under rapid stirring (>90 rpm), charge the reactor with the contents of the 5 L Schott bottle containing the relacorilant solution over at least 30 minutes using the dosing pump through the reagent addition line (note that the stirring is approximately 160 rpm during the addition, and reduced to approximately 50 rpm after the addition is complete). 47. Stir the reactor contents at 20°C for at least 12 hours. 48. A sample is removed from the reactor, filtered, and analyzed by HPLC to determine the concentration of relacorilant in the liquid. 49. Stop the agitation, drain the reactor contents into a filter, and collect the liquid in a plastic-lined drum of known mass. 50. Purified water (2.34 Kg) is charged to the reactor through the solvent addition line using the dosing pump. 51. Stir the reactor contents at 20°C for at least 5 minutes. 52. Stop the agitation, drain the reactor contents into a filter, and collect the liquid in a plastic-lined drum of known mass. 53. Dewater the filter cake in the filter with nitrogen for at least 10 minutes. 54. Transfer the solids from the filter to a clean looking tray and place the tray in the dryer. 55. Turn on the dryer and set the temperature to 50°C. 56. Dry the solids in the dryer under vacuum with a nitrogen bleed for a minimum of 15 hours. 57. Transfer the solids from the dryer into clean, double-bagged, antistatic polyethylene liner bags of known weight with two desiccant pouches between the liner bags, and place the liner bags into an HDPE keg. 58. Yield: 606g, 97.0%.

[0242] Characterization data for the title compound was consistent with that of Example 18 of US Pat. No. 8,859,774.

[0243] Example 5. Purity Profile The impurity profiles of the compounds of Examples 3 and 4 were determined. [Table 5] [Table 6]

[0244] Example 6. Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone oxalate [ka] Approximately 180 mg of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone was dissolved in acetonitrile to form a stock solution. Separately, oxalic acid was dissolved in acetonitrile and added to the stock solution in an equimolar amount. The resulting oil was crystallized. The crystals were then washed with 5 mL of acetonitrile using a Buchner funnel and flask. The crystals were then dried under a nitrogen stream using a Buchner funnel and flask for 3 hours. [Table 7]

[0245] Example 7. Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone tris-hydrochloride [ka] The Boc deprotection and crystallization procedure from Scheme 5 is described below. 1. A vessel was charged with 1 (16.0 g, 95.1 wt%, 28.05 mmol, 1.0 equiv) and MeCN (80 mL, 5 vol) and cooled to 0°C. 2. HCl (3M in CPME, 36.8 mL, 112.2 mmol, 4.0 equiv) was added over 2 min, maintaining the internal temperature below 10°C. 3. The reaction mixture was warmed to room temperature and aged for 20 hours. The reaction conversion was determined to be 98% by HPLC LCAP (FFCAM method). 4. DIPEA (2.0 mL, 11.7 mmol, 0.4 equiv) was added over 30 seconds at room temperature. 5. The reaction mixture was seeded with 2·HCl (approximately 5 mg) and aged at room temperature for 20 min. 6. DIPEA (7.1 mL, 44.4 mmol, 1.5 equiv) was added over 45 min at room temperature using a syringe pump and aged for an additional 30 min. The loss of 2 in solution was determined by HPLC to be 19.9 mg / mL. 7. The antisolvent IPAC (96 mL, 6 volumes) was added over 1 hour and the slurry was aged at room temperature for 16 hours. The loss of 2 in solution was 8.2 mg / mL as determined by HPLC. 8. The slurry was cooled to -20°C and aged for 2 hours. The loss of 2 in solution was 7.8 mg / mL as determined by HPLC. 9. The slurry was filtered under N, deliquinated with MeCN (16 mL, 1 vol), and dried under vacuum at 40 °C for 16 h to give 2·HCl as a white crystalline solid in 72% isolated yield (9.57 g, LCAP purity 99.6, 93.3 wt% relative to 2). The mother liquor contained 2 in 13% assay yield. [Table 8]

[0246] Example 8. Preparation of [(4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-[(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl]-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)-2-pyridinyl)methanone [ka] The target compound was prepared using the following steps.

[0247] The tris-MSA salt from step 2 was suspended in ethyl acetate and cooled to 0°C. Triethylamine (4.1 equivalents) was then charged to form a solution, followed by the addition of 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (1.0 equivalents). Once the reaction was complete as determined by HPLC, excess sulfonyl chloride was removed by reaction with a scavenger (N-methylpiperazine, 0.25 equivalents). The reaction was then worked up by washing with 1 M aqueous hydrochloric acid, followed by 3% (w / w) aqueous sodium bicarbonate. A solvent exchange to ethanol was performed, and the title compound precipitated as an amorphous solid from a mixture of ethanol, acetone, and water. The title compound was isolated by filtration, washed with water, and dried under vacuum at elevated temperature. 1. The container was washed with ethyl acetate and dried under vacuum. 2. The Tris MSA salt from Step 2 [12.81 kg (corrected to 7.81 kg)] and ethyl acetate (161.6 kg) were charged to a vessel and the contents were cooled to 0°C. 3. While maintaining the batch temperature at <5°C, triethylamine (7.32 kg) was charged to the vessel over 10 minutes, rinsing the lines with ethyl acetate. 4. The contents were aged for >1 hour at <5°C. 5. While maintaining the batch temperature, a stream of 47.0 kg (3.20 kg corrected) of ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride acetate was charged to the vessel. 6. The contents were warmed to 20°C over 25 minutes and aged at this temperature for 2 hours. 7. The conversion was analyzed by HPLC. 8. N-methylpiperazine (0.44 kg) was charged to the vessel over a period of 5 minutes. 1. The batch was aged at 20°C for 16 hours. 9. 1.0 M HCl solution (129.3 kg) was charged to the vessel and allowed to settle into the biphasic mixture, and the aqueous layer was drained. This step was repeated again. 10. A 1.0 M HCl solution (64.6 kg) was charged to the vessel and allowed to settle into the biphasic mixture, and the aqueous layer was drained. An 11.3 wt % sodium bicarbonate solution (65.3 kg) was charged to the vessel and allowed to settle into the biphasic mixture, and the aqueous layer was drained. 12. Purified water (64.0 kg) was charged to the vessel and allowed to settle into the biphasic mixture, and the aqueous layer was drained. This step was repeated again. 13. The solution of the title compound was discharged into two drums. 14. The solution of the title compound was charged to a second vessel through an in-line filter and concentrated under reduced pressure from approximately 190 L to 38 L, maintaining the batch temperature below 45°C. 15. Ethanol (151.3 kg) was charged to the vessel and the stream was concentrated from approximately 230 L to 38 L under reduced pressure while maintaining the batch temperature below 45°C. 16. The solution of the title compound was transferred to a clean plastic-coated drum. 17. Purified water (230.6 kg) was charged to the vessel through an in-line filter. 18. The solution of the title compound was charged to the vessel over 30 minutes. The slurry was aged for 30 minutes to ensure no gumming occurred. 19. The slurry was filtered and the filter cake was washed with purified water (37.9 Kg). 20. The wet filter cake was dewatered under a stream of nitrogen. 21. The wet filter cake was dried in a vacuum oven at 40°C.

[0248] The title compound was isolated as an off-white solid. Total yield: 9.810 kg (94.6% yield). Characterization data for the title compound was consistent with that of Example 11CE of U.S. Pat. No. 8,859,774.

[0249] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall control.

Claims

1. A compound of formula J: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) a compound of formula IIb: 【Chemistry 2】 and the following sulfonyl chlorides: 【Chemistry 3】 to prepare a compound of formula J in at least 60% yield and at least 98% purity; During the ceremony, X １ is -CH= or -N=, HX is HBr or 【change】 an acid solvate wherein R 1 is C 1-6 alkyl, C 1-10 haloalkyl, phenyl, or 4-methylphenyl; The method wherein the subscript n is 1 to 4.

2. A compound of formula I: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, (a) a compound of formula IIb: 【Chemistry 5】 and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: 【Chemistry 6】 to prepare a compound of Formula I in at least 60% yield and at least 98% purity; During the ceremony, HX is an acid solvate, The method of claim 1, wherein the subscript n is 1 to 4.

3. 2. The method of claim 1, wherein HX is HBr.

4. A compound of formula I: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, (a) a compound of formula IIb-1: 【Chemistry 8】 and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: 【Chemistry 9】 to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: 【Chemistry 10】 4. The method of claim 3, wherein the subscript n is 1 to 4.

5. The method of claim 4 , wherein the first reaction mixture further comprises a non-nucleophilic amine base.

6. 6. The method of claim 5, wherein the non-nucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof.

7. 5. The method of claim 4, wherein the sulfonyl chloride is present in a molar ratio of 1.2 to 2.3 relative to the compound of formula IIb-1.

8. The compound of formula I is (b) a compound of formula IIa: 【Chemistry 11】 and gaseous HBr to form a compound of Formula IIb-1 having the structure: 【Chemistry 12】 (a) a compound of formula IIb-1, , triethylamine, and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: 【Chemistry 13】 wherein the sulfonyl chloride is present in a molar ratio of about 1.2 relative to the compound of Formula IIb-1; (a1) combining the first reaction mixture with water having a pH of 4-5 to form a first organic phase and a first aqueous phase; (a2) mixing the first organic phase with water and sodium chloride having a pH of 5-6; (a3) mixing the first organic phase and silica gel to prepare the compound of formula I in a yield of at least 60% and with a purity of at least 98%, wherein the compound of formula I contains less than 1% (w / w) of the compound of formula X-5: 【Chemistry 14】

9. The compound of formula IIa is (c) a Grignard reagent, a compound of formula III: 【Chemistry 15】 and 2-bromo-4-(trifluoromethyl)pyridine: 【Chemistry 16】 wherein the pyridine is present in a molar ratio of 1.0 to 1.5 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 relative to the compound of formula III, thereby preparing the compound of formula IIa.

10. 10. The method of claim 9, wherein the Grignard reagent comprises iPrMgCl or iPrMgBr.

11. 10. The method of claim 9, wherein the third reaction mixture further comprises a third solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene.

12. (c1) adding an acid and water to the third reaction mixture to form a work-up treatment mixture; 10. The method of claim 9, further comprising: (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa, 2-methyltetrahydrofuran in an amount less than 100 ppm, and water in an amount less than 0.5% (w / w).

13. 13. The method of claim 12, wherein the acid comprises formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or a mixture thereof.

14. The method for preparing the compound of formula I comprises: (c) iPrMgBr, 2-methyltetrahydrofuran, toluene, and a compound of formula III: 【Chemistry 17】 and 2-bromo-4-(trifluoromethyl)pyridine: 【Chemistry 18】 wherein the pyridine is present in a molar ratio of about 1.4 relative to the compound of formula III and the Grignard reagent is present in a molar ratio of about 1.65 relative to the compound of formula III to prepare a compound of formula IIa: 【Chemistry 19】 (c1) adding acetic acid and water to the third reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIa, 2-methyltetrahydrofuran in an amount of less than 100 ppm, and water in an amount of less than 0.5% (w / w); (b) forming a second reaction mixture comprising the intermediate mixture and gaseous HBr to form a compound of Formula IIb-1 having the following structure: 【Chemistry 20】 (a) Reacting the compound of formula IIb-1 with triethylamine and the following 1-methyl-1H-pyrazole-4-sulfonyl chloride: 【Chemical 21】 wherein the sulfonyl chloride is present in a molar ratio of about 1.2 relative to the compound of formula IIb-1, to prepare a compound of formula I in at least 60% yield and at least 98% purity, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5: 【Chemical 22】

15. The method further comprises, after step (a), (a1) combining the first reaction mixture with water having a pH of 4-5 to form a first organic phase and a first aqueous phase; (a2) mixing the first organic phase with water and sodium chloride having a pH of 5-6; 15. The method of claim 14, further comprising: (a3) combining the first organic phase with silica gel.

16. A compound of formula I: 【Chemical 23】 or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) (i) a first mobile phase mixture comprising water in an amount of at least 95% (v / v), formic acid in an amount of 0.05-0.2% (v / v), and acetonitrile in an amount of 1-5% (v / v); (ii) a second mobile phase mixture comprising water in an amount of 45-55% (v / v), formic acid in an amount of 0.01-0.1% (v / v), and acetonitrile in an amount of 45-55% (v / v); and (iii) eluting the compound of Formula I by high performance liquid chromatography on a C18 column using a third mobile phase comprising water in an amount of 5 to 15% (v / v), formic acid in an amount of 0.005 to 0.02% (v / v), and acetonitrile in an amount of at least 85% (v / v); forming an elution mixture comprising a compound of formula I having a purity of at least 98% and a compound of formula X-5 below in an amount of less than 0.75% (w / w); 【Chemistry 24】 (a1) extracting the compound of Formula I from the elution mixture into ethyl acetate to form an extraction mixture; (a2) mixing the extraction mixture with methyl t-butyl ether (MTBE) under vacuum to form an MTBE mixture containing less than 5% (v / v) ethyl acetate; (d) filtering the MTBE mixture through a filter; a compound of formula I, the compound of formula X-5 in an amount of less than 0.5% (w / w), a compound of formula X-4 in an amount of less than 0.3% (w / w): 【Chemistry 25】 and a compound of formula X-6 in an amount of less than 0.25% (w / w): 【Chemical 26】 forming a filtered MTBE mixture comprising: (e) adding the filtered MTBE mixture to heptane to form a precipitated compound of Formula I containing 1,4-dibromopentane in an amount less than 20 ppm; (f) dissolving the precipitated compound of formula I in methanol to form a methanol mixture; (g) adding the methanol mixture to water to precipitate the purified compound of Formula I, wherein the purified compound of Formula I has a purity of at least 99%; and a compound of formula X-5 in an amount of less than 0.5% (w / w); 1,4-dibromopentane in an amount less than 6 ppm; less than 6 ppm of the following: methyl 1-methyl-1H-pyrazole-4-sulfonate; 【Chemical 27】 and precipitating the purified compound of Formula I, wherein the purified compound contains less than 6 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. 【Chemical Formula 28】

17. A purified compound of Formula I has a purity of at least 99%; and Methyl bromide in an amount less than 20 ppm; 2-bromopropane in an amount less than 20 ppm.

18. A purified compound of Formula I has a purity of at least 99%; and Methyl bromide in an amount less than 8 ppm; 2-bromopropane in an amount less than 8 ppm; and 1,4-dibromopentane in an amount less than 8 ppm.

19. A purified compound of Formula I has a purity of at least 99%; and less than 6 ppm of the following: ethyl 1-methyl-1H-pyrazole-4-sulfonate; 【Chemical 29】 and an amount of less than 6 ppm of the following: isopropyl 1-methyl-1H-pyrazole-4-sulfonate. 【Chemistry 30】

20. A purified compound of Formula I has a purity of at least 99%; and a compound of formula X-4 in an amount of less than 0.1% (w / w); a compound of formula X-5 in an amount of less than 0.2% (w / w); a compound of formula X-6 in an amount of less than 0.2% (w / w); Methyl bromide in an amount less than 4 ppm; 2-bromopropane in an amount less than 4 ppm; 1,4-dibromopentane in an amount less than 4 ppm; 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 4 ppm; methyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm; ethyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm; 17. The method of claim 16, comprising isopropyl 1-methyl-1H-pyrazole-4-sulfonate in an amount less than 4 ppm.

21. HX is 【Chemical 31】 and During the ceremony, R １ is C １～６ Alkyl, C １～１０ haloalkyl, phenyl, or 4-methylphenyl; The method of claim 1, wherein the subscript n is 1 to 4.

22. A compound of formula J: 【Chemical 32】 or a pharmaceutically acceptable salt thereof, (a) a compound of formula IIb-2: 【Chemical 33】 and the following sulfonyl chlorides: 【Chemical 34】 to prepare a compound of formula J in at least 75% yield and at least 98% purity; During the ceremony, X １ is -CH= or -N=, R １ is C １～６ Alkyl, C １～１０ haloalkyl, phenyl, or 4-methylphenyl; 22. The method of claim 21, wherein the subscript n is 1 to 4.

23. A compound of formula I: 【Chemistry 35】 or a pharmaceutically acceptable salt thereof, comprising the steps of: (c) tetrahydrofuran, toluene, iPrMgCl, and a compound of formula III: 【Chemical 36】 and 2-bromo-4-(trifluoromethyl)pyridine: 【Chemical 37】 wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of Formula III and the Grignard reagent is present in a molar ratio of about 3.05 relative to the compound of Formula III; (c1) adding acetic acid and water to the sixth reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of Formula IIa: 【Chemical 38】 (b) the intermediate mixture; forming a fifth reaction mixture comprising acetonitrile, and methanesulfonic acid to form a compound of formula IIb-2: 【Chemical Formula 39】 (a) a compound of formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: 【Chemistry 40】 wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2; (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the reaction mixture to precipitate the compound of formula I in at least 75% yield and at least 98% purity.

24. A compound of formula Ia: 【Chemistry 41】 or a pharmaceutically acceptable salt thereof, comprising the steps of: (c) tetrahydrofuran, toluene, iPrMgCl, and a compound of formula III: 【Chemistry 42】 and 2-bromo-4-(trifluoromethyl)pyridine: 【Chemistry 43】 wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of Formula III and the Grignard reagent is present in a molar ratio of about 3.05 relative to the compound of Formula III; (c1) adding acetic acid and water to the sixth reaction mixture to form a work-up mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of Formula IIa: 【Chemical 44】 (b) the intermediate mixture; forming a fifth reaction mixture comprising acetonitrile, and methanesulfonic acid to form a compound of formula IIb-2: 【Chemistry 45】 (a) a compound of formula IIb-2, triethylamine, ethyl acetate, and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: 【Chemistry 46】 wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2; (a1) adding methanol to the fourth reaction mixture; (a2) adding water to the reaction mixture to precipitate the compound of Formula Ia in at least 75% yield and at least 98% purity.

25. 1. A composition comprising: in an amount of at least 99% (w / w) of a compound of formula I: 【Chemistry 47】 and one or more impurities in an amount of 0.01-1% (w / w).

26. The impurities are a compound of formula X-D in an amount of less than 0.40% (w / w): 【Chemistry 48】 and a compound of formula XE in an amount of less than 0.40% (w / w): 【Chemistry 49】 26. The composition of claim 25, further comprising:

27. 1. A composition comprising: in an amount of at least 99% (w / w) of a compound of formula Ia: 【Chemistry 50】 and one or more impurities in an amount of 0.01-1% (w / w).

28. 27. A pharmaceutical composition comprising the composition of claim 25 or 26 and one or more pharmaceutically acceptable excipients.

29. 29. The pharmaceutical composition of claim 28 for treating a disorder or condition by modulating the glucocorticoid receptor.

30. 29. The pharmaceutical composition of claim 28 for treating a disorder or condition by antagonizing the glucocorticoid receptor.

31. 29. The pharmaceutical composition of claim 28 for treating fatty liver disease.

32. 29. The pharmaceutical composition of claim 28 for treating antipsychotic-induced weight gain.

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