Process for preparing heteroaryl-ketone fused aza-naphthane glucocorticoid receptor modulators

Abstract

The present invention provides methods of preparing heteroaryl-ketone fused azanaphthane glucocorticoid receptor modulators, as well as compositions having low impurity levels.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 367,151, filed on June 28, 2022, which is incorporated herein in its entirety for all purposes. Background Art

[0003] There are two types of high affinity receptors 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 (adrenocorticotropic hormone), which shows circadian variation and increases in response to stress and food. Cortisol levels respond within minutes to many physical and physiological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and exerts its effects by binding to intracellular glucocorticoid receptors (GR). In humans, the glucocorticoid receptor exists in two forms: a 777 amino acid ligand-binding GR-α; and a GR-β isoform that lacks 50 carboxyl-terminal residues. Since these include a ligand-binding domain, GR-β cannot bind to a ligand, is constantly located in the nucleus and has no transcriptional activity. GR is also known as GR-II.

[0004] Receptor modulators (such as agonists, partial agonists, and antagonists) can be used to modulate the biological effects of Cortisol at the GR level, including those caused by hypercortisolism. Several different types of agents are capable of blocking the physiological effects of GR agonist binding. These antagonists include compositions that inhibit the ability of agonists to effectively bind to and / or activate GR by binding to GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) Journal of Clinical Endocrinology and Metabolism (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) Annals of Medicine (Annu. Rev. Med.) 48:129). Dazucorilant (CORT113176) is another such glucocorticoid receptor modulator compound and has been previously described in PCT Publication No. WO 2013 / 177559 and U.S. Pat. No. 8,859,774. There is a need in the art for new methods of preparing dazucorilant with lower impurity levels. Surprisingly, the present invention meets these and other needs. Summary of the invention

[0005] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] The method comprises:

[0008] (a) forming a compound comprising formula II:

[0009]

[0010] 4-(Trifluoromethyl)benzenesulfonyl chloride:

[0011] to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%,

[0012] in

[0013] HX is an acid solvate; and

[0014] The subscript n is 1 to 4.

[0015] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0016]

[0017] The method comprises:

[0018] (a) forming a compound comprising formula IIa:

[0019] and

[0020] 4-(Trifluoromethyl)benzenesulfonyl chloride:

[0021] to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%,

[0022] in

[0023] R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and

[0024] The subscript n is 1 to 4.

[0025] In some embodiments, the present invention provides a method for preparing a compound of formula IIb:

[0026]

[0027] The method comprises the steps of:

[0028] (c) forming a compound of formula III comprising a Grignard reagent:

[0029] and

[0030] 2-Bromo-pyridine:

[0031] The third reaction mixture,

[0032] wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of formula III, to prepare the compound of formula IIb.

[0033] In some embodiments, the present invention provides a composition comprising:

[0034] An amount of at least 99% of a compound of formula I:

[0035] and

[0036] One or more impurities in an amount of 0.01 to 1%.

[0037] In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid:

[0038]

[0039] It is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 7.8° 2-θ ± 0.2° 2-θ, 14.6° 2-θ ± 0.2° 2-θ, and 15.5° 2-θ ± 0.2° 2-θ.

[0040] In some embodiments, the present invention provides a pharmaceutical composition comprising the low impurity composition of the present invention and a pharmaceutically acceptable excipient.

[0041] In some embodiments, the present invention provides a method of treating a disorder or condition by modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a low impurity composition of the present invention or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0042] In some embodiments, the present invention provides a method of treating a disorder or condition by antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a low impurity composition of the invention or a pharmaceutical composition of the invention.

[0043] In some embodiments, the present invention provides a method for treating amyotrophic lateral sclerosis (ALS), comprising administering a therapeutically effective amount of a low impurity composition of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof, thereby treating fatty liver disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 A synthetic scheme for preparing (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone according to Example 1 is shown.

[0045] Figure 2 Shown is an X-ray diffraction pattern (XRPD) of crystalline compound (R)-1-(4-fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium methanesulfonate.

[0046] Figure 3 Shown is a differential scanning calorimetry (DSC) thermogram of crystalline compound (R)-1-(4-fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium methanesulfonate.

[0047] Figure 4 Shown is the thermogravimetric analysis (TGA) of crystalline compound (R)-1-(4-fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium methanesulfonate. DETAILED DESCRIPTION

[0048] I. Summary

[0049] The present disclosure describes a novel method for preparing compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (dazoclinic) of formula I with lower impurity levels than previously described methods. The novel method for preparing dazoclinic has improved safety and cost effectiveness compared to known methods and can be prepared on a larger scale. Dazoclinic can be prepared as in Example 1 of U.S. Patent No. 8,859,774. The present disclosure also describes compositions of dazoclinic having lower impurity levels.

[0050] II. Definitions

[0051] When referring to a value, "about" includes the value + / - 10% of the value. For example, about 50% includes a range of 45% to 55%, and about 20 molar equivalents includes a range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to each of the values ​​at each end of the range + / - 10% of the value. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0052] "Forming a reaction mixture" refers to the process of contacting at least two different substances so that they mix together and can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate from one or more added reagents, which can be produced in the reaction mixture.

[0053] "Dissolve," "dissolving," or "dissolution" refers to a solid material that is substantially soluble in a particular solvent. For example, the solid material may be greater than 90% soluble in the solvent, or greater than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or greater than 99% soluble in the solvent.

[0054] "Distilling, distill or distillation" refers to the separation of components in a liquid mixture using a combination of temperature and pressure. The target component is converted from a liquid to a gas, and then the gas is condensed back into a liquid to separate the target component from the other components of the mixture.

[0055] "Elution", "elution" or "elution" refers to the process of separating a target component from other components in a mixture by passing the mixture through a stationary phase. The target component is eluted from the stationary phase using a mobile phase that may contain any suitable solvent or acid.

[0056] "Concentrate" or "Concentrating" refers to the process of removing a solvent or diluent from a mixture to increase the molar concentration of the components in the mixture. Concentration can be accomplished by a variety of methods, such as distillation or rotary evaporation. Concentration can include removing some or all of the solvent or diluent.

[0057] "Precipitate," "precipitated," or "precipitation" refers to a solid formed from a solution, for example, by adding a first solvent in which a compound is dissolved to an excess of a second solvent in which the compound is substantially insoluble, causing the dissolved compound to flow out of solution and form a solid.

[0058] "Substantially free" refers to a composition having undesired components in an amount less than 5%, less than 1%, less than 0.5%, or even less than 0.1% by HPLC peak area.

[0059] "Aqueous phase" refers to a mixture containing water.

[0060] "Organic phase" refers to a mixture containing a water-miscible or immiscible solvent that is capable of dissolving either or both of 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 be non-polar aprotic solvents, polar aprotic solvents, and polar protic solvents. Representative solvents include, but are not limited to, pentane, hexane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, dichloromethane, chloroform, and the like.

[0061] "Acid" means an acid capable of donating a proton (H + ) or a compound defined as an electron pair acceptor according to Lewis. The acid that can be used in the present invention is a Bronsted-Lowry acid, which includes but is not limited to alkanoic acid or carboxylic acid (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acid and mineral acid as defined herein. Mineral acid is an inorganic acid such as a hydrohalide (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), a halogen oxygen-containing acid (hypochlorous acid, perchloric acid, etc.) and sulfuric acid, nitric acid, phosphoric acid, chromic acid and boric acid. Sulfonic acid includes methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, etc.

[0062] "Grignard reagent" refers to a reagent containing a complex of magnesium metal, a halide, and an alkyl ligand that is capable of forming a carbon-carbon bond. Representative Grignard reagents include, but are not limited to, iPrMgCl and iPrMgBr.

[0063] "Non-nucleophilic base" refers to a base that is moderate to strong but at the same time weakly nucleophilic. Representative non-nucleophilic bases include bases such as potassium carbonate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine and quinuclidine. Non-nucleophilic bases include non-nucleophilic amine bases.

[0064] "Solvent" refers to a substance that can dissolve a solute, such as a liquid. A solvent can be polar or non-polar, protic or non-protic. Polar solvents generally have a dielectric constant greater than about 5 or a dipole moment higher than about 1.0, and non-polar 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 that can be used to remove, such as having a hydroxyl or carboxyl group. Non-protic solvents lack such groups. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.) and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, 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 can be used in the present invention.

[0065] "Room temperature" is the range of air temperature generally considered suitable for human occupancy, or between approximately 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0066] "Vacuum" or "reduced pressure" refers to a pressure less than atmospheric pressure. Atmospheric pressure measures about 1013 mbar, 760 mm Hg, or about 14.7 psi. Thus, a vacuum can be less than 1013 mbar, or less than 100, 10, 1, 0.1, or less than 0.01 mbar.

[0067] "Alkyl" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms. Alkyl groups may contain any number of carbon atoms, such as 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 For example, 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 an alkyl group having up to 20 carbon atoms, such as but not limited to heptyl, octyl, nonyl, decyl, etc. The alkyl group can be substituted or unsubstituted.

[0068] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0069] "Haloalkyl" refers to an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to alkyl, a haloalkyl group may have any suitable number of carbon atoms, such as C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. The term "perfluoro" may be used to define a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0070] "Pharmaceutically acceptable salt" refers to an acid or base salt of a compound used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts include inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, methanesulfonic acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional 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.

[0071] As used herein, "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of 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 recipients thereof.

[0072] "Pharmaceutically acceptable excipient" refers to a substance that facilitates administration of an active agent to a subject and absorption by the subject. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavoring agents, and pigments. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0073] "Treat," "treating," and "treatment" refer to any marker of success in treating or ameliorating an injury, condition, or disorder, including any objective or subjective parameter, such as relief; remission; reducing symptoms or making an injury, condition, or disorder more tolerable to the patient; slowing the rate of degeneration or decline; making the final stages of degeneration less debilitating; improving the patient's physical or mental health. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0074] "Administering" refers to administering to a subject orally, administering as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous, intrathecally, or implanting a slow release device such as a mini-osmotic pump.

[0075] "Patient" or "subject" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammalian animals. In some embodiments, the patient is a human.

[0076] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease or condition, or to show a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., 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).

[0077] "Glucocorticoid receptor" ("GR") refers to one of a family of intracellular receptors that specifically binds Cortisol and / or Cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. 2005 Oct. 1 35 283-292). Glucocorticoid receptor is also known as Cortisol receptor. The term encompasses isoforms of GR, recombinant GR, and mutant GR.

[0078] The Cortisol receptor is a glucocorticoid receptor (GR), in particular a type II GR, which specifically binds Cortisol and / or Cortisol analogs such as dexamethasone (see, for example, Turner & Muller, J. Mol. Endocrinol. 2005 Oct 1 35 283-292).

[0079] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (GR I) that is activated by aldosterone in humans.

[0080] "Glucocorticoid receptor modulator" (GMM) refers to any compound that regulates any biological response related to the binding of glucocorticoid receptors to agonists. As used herein, with respect to GRM, glucocorticoid receptors can be GR or both. For example, GRMs acting as agonists such as dexamethasone increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (hepatocellular carcinoma cell lines of human liver; ECACC, UK). GRMs acting as antagonists such as mifepristone inhibit the increase in agonist-induced tyrosine aminotransferase (TAT) activity in HepG2 cells. TAT activity can be measured as listed in literature A.Ali et al., J.Med.Chem., 2004, 47, 2441-2452.

[0081] "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. Therefore, GR antagonists may be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity may be measured as listed in A.Ali et al., J.Med.Chem., 2004, 47, 2441-2452. Inhibitors are IC 50 Compounds having a (half maximal inhibitory concentration) of less than 10 micromolar. See Example 1 of US Patent 8,685,973, the entire contents of which are hereby incorporated by reference in their entirety.

[0082] "Modulate" and "modulating" are used according to their ordinary plain meanings and refer to the act of changing or altering one or more properties. "Modulate" refers to the process of changing or altering one or more properties. For example, when applied to the effect of a modulator on a target protein, modulating refers to changing by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0083] "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 a molecular target.

[0084] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist at a receptor molecule or inhibiting the signal produced by a receptor-agonist. Receptor antagonists inhibit or reduce agonist-mediated responses, such as gene expression.

[0085] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. The 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, the inhibition is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more of the expression or activity in the absence of the antagonist.

[0086] "Inhibition," "inhibits," and "inhibitors" refer to a compound or method that inhibits a specific action or function.

[0087] "Disorder" or "condition" refers to a condition or health condition of a patient or subject that can be treated with a glucocorticoid receptor modulator of the invention. In some embodiments, examples of disorders or conditions include, but are not limited to, amyotrophic lateral sclerosis (ALS).

[0088] III. Method for preparing formula I from formula IIA

[0089] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0090]

[0091] The method comprises:

[0092] (a) forming a compound comprising formula II:

[0093]

[0094] 4-(Trifluoromethyl)benzenesulfonyl chloride:

[0095] to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%,

[0096] wherein HX is an acid solvate; and subscript n is 1 to 4.

[0097] In some embodiments, HX is

[0098]

[0099] Where R1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl or

[0100]

[0101] In some embodiments, HX is

[0102]

[0103] Where R 1 C 1-6 Alkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl or

[0104]

[0105] In some embodiments, HX is

[0106]

[0107] Where R 1 C 1-6 Alkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl or

[0108]

[0109] In some embodiments, HX is

[0110]

[0111] Where R 1 C 1-6 alkyl.

[0112] In some embodiments, HX is MeS(O)2OH,

[0113]

[0114] In some embodiments, HX is MeS(O)2OH.

[0115] In some embodiments, the present invention provides a method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0116]

[0117] The method comprises:

[0118] (a) forming a compound comprising formula IIa:

[0119] and

[0120] 4-(Trifluoromethyl)benzenesulfonyl chloride:

[0121] to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%,

[0122] Where R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and the subscript n is 1 to 4.

[0123] In some embodiments, the compound of Formula I contains less than 1% of the compound of Formula X-5:

[0124]

[0125] Compounds of formula I can be prepared from compounds of formula IIa:

[0126]

[0127] A. Preparation of Formula I from Formula IIa

[0128] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0129]

[0130] The method comprises:

[0131] (a) forming a compound comprising formula IIa:

[0132] and

[0133] 4-(Trifluoromethyl)benzenesulfonyl chloride:

[0134] to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%,

[0135] in

[0136] R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and

[0137] The subscript n is 1 to 4.

[0138] In some embodiments, the compound of Formula I is prepared in at least 75% yield and at least 98% purity.

[0139] In some embodiments, R 1 C 1-2 Alkyl, C 1-2 In some embodiments, R 1 is methyl, ethyl, -CF3, phenyl or 4-methylphenyl. In some embodiments, R 1 It is methyl.

[0140] Subscript n can be 1, 2, 3, or 4. In some embodiments, subscript n is 1. In some embodiments, subscript n is 2. In some embodiments, subscript n is 3. In some embodiments, subscript n is 4. In some embodiments, the compound of Formula IIa has the structure:

[0141]

[0142] 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 includes trimethylamine, triethylamine (Et3N), N, N-diisopropylethylamine (iPr2NEt; DIPEA), N, N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N, N-dimethylaniline, N, N-diethylaniline, 2,6-lutidine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinylpyridine, 1,4-diazabicyclo [2.2.2] octane (DABCO) or a mixture thereof. In some embodiments, the non-nucleophilic amine base includes triethylamine.

[0143] The first reaction mixture may include any suitable solvent. For example, the solvent may be an organic solvent including but not limited to ethyl acetate, isopropyl acetate and n-butyl acetate. In certain embodiments, the first reaction mixture may also include a first solvent. In certain embodiments, the first solvent includes ethyl acetate, isopropyl acetate, n-butyl acetate or a mixture thereof. In certain embodiments, the first reaction mixture may also include ethyl acetate.

[0144] The sulfonyl chloride used in the first reaction mixture can be present in any suitable molar ratio with the compound of formula II or formula IIa. For example, sulfonyl chloride can be present in a molar ratio of 0.5 to 2.0 with the compound of formula II or formula IIa, 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 with the molar ratio of the compound of formula II or formula IIa. In certain embodiments, sulfonyl chloride is present in a molar ratio of 0.5 to 1.5 with the compound of formula IIa. 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 with the compound of formula II or formula IIa. In certain embodiments, sulfonyl chloride can be present in a molar ratio of about 1.0 with the compound of formula IIa.

[0145] 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%.

[0146] 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%.

[0147] In some embodiments, the method for preparing the compound of formula I further comprises the step of: (a1) adding an amino scavenger to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride. The amino scavenger can be any suitable amino compound capable of reacting with sulfonyl chloride. In some embodiments, the amino scavenger includes N-methylpiperazine, N- 1 ,N 1 -Dimethylethane-1,2-diamine, N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine or N 1 ,N 1 -bis(2-aminoethyl)ethane-1,2-diamine. In some embodiments, the amino scavenger comprises N-methylpiperazine. In some embodiments, the amino scavenger is N-methylpiperazine.

[0148] The reducing agent may be present in any suitable amount. For example, the amino scavenger may be present in a molar ratio of less than 1.0 to the compound of Formula II or Formula IIa, or in a molar ratio of less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, or less than 0.25 to the compound of Formula II or Formula IIa. In some embodiments, the amino scavenger is present in a molar ratio of about 0.25 to the compound of Formula IIa.

[0149] In some embodiments, the method for preparing a compound of formula I further includes the steps of: (a2) adding a first acid and water to the first reaction mixture to separate the first reaction mixture into a first aqueous mixture and a first organic mixture; and (a3) ​​separating the first aqueous mixture from the first organic mixture.

[0150] The first acid can include any suitable acid. In some embodiments, the first acid includes hydrochloric acid.

[0151] In some embodiments, the method of preparing the compound of Formula I further comprises the steps of:

[0152] (a4) concentrating the first organic mixture;

[0153] (a5) adding ethanol to the concentrated first organic mixture; and

[0154] (a6) adding water to the concentrated first organic mixture to precipitate the compound of Formula I. In some embodiments, the method for preparing the compound of Formula I from the compound of Formula IIa comprises the steps of:

[0155] (a) forming a compound of formula IIa having the structure:

[0156]

[0157] Triethylamine, ethyl acetate and 4-(trifluoromethyl)benzenesulfonyl chloride: the first reaction mixture,

[0158] wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of formula IIa;

[0159] (a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride;

[0160] (a2) adding HCl and water to the first reaction mixture to separate the first reaction mixture into the first aqueous mixture and the first organic mixture;

[0161] (a3) separating the first aqueous mixture from the first organic mixture;

[0162] (a4) concentrating the first organic mixture;

[0163] (a5) adding ethanol to the concentrated first organic mixture; and

[0164] (a6) adding water to the concentrated first organic mixture to precipitate the compound of formula I with a yield of at least 75% and a purity of at least 98%.

[0165] The compounds of formula I can be prepared using any acceptable amount of formula X-5:

[0166]

[0167] For example, a compound of Formula I containing less than 5%, or 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 less than 0.1% of a compound of Formula X-5 can be prepared. In some embodiments, a compound of Formula I containing less than 1% of a compound of Formula X-5 can be prepared:

[0168]

[0169] In some embodiments, a compound of Formula I can be prepared that contains less than 0.75% of a compound of Formula X-5. In some embodiments, a compound of Formula I can be prepared that contains less than 0.5% of a compound of Formula X-5. In some embodiments, a compound of Formula I can be prepared that contains less than 0.1% of a compound of Formula X-5.

[0170] B. Preparation of Formula IIa from Formula IIb

[0171] The compound of formula IIa can be prepared from the compound of formula IIb. In some embodiments, the present invention provides a method for preparing the compound of formula IIa:

[0172]

[0173] The method comprises:

[0174] (b) forming a compound comprising Formula IIb:

[0175] and

[0176] Sulfonic acid of the formula:

[0177] A second reaction mixture,

[0178] To form the compound of formula IIa,

[0179] in

[0180] R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and

[0181] The subscript n is 1 to 4.

[0182] Subscript n can be 1, 2, 3, or 4. In some embodiments, subscript n is 1. In some embodiments, subscript n is 2. In some embodiments, subscript n is 3. In some embodiments, subscript n is 4. In some embodiments, the compound of Formula IIa has the structure:

[0183]

[0184] The second reaction mixture may include any suitable solvent. In certain embodiments, the second reaction mixture includes the second solvent. The second solvent may include but is not limited to pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride and chloroform. In certain embodiments, the second solvent includes acetonitrile, cyclopentyl methyl ether (CPME), tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), methanol, ethanol, diethyl ether, methyl tert-butyl ether (MTBE), toluene or its combination. In certain embodiments, the second reaction mixture includes acetonitrile.

[0185] C. Preparation of Formula IIb from Formula III

[0186] The compound of formula IIb can be prepared by a variety of methods. In some embodiments, the compound of formula IIb can be prepared by the following steps:

[0187] (c) forming a compound of formula III comprising a Grignard reagent:

[0188] and

[0189] 2-Bromo-pyridine:

[0190] The third reaction mixture,

[0191] wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of formula III, to prepare the compound of formula IIb.

[0192] 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.

[0193] The Grignard reagent can be present in any suitable molar ratio with 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, 2.9 to 3.1 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.8 to 3.3 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.9 to 3.2 with 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 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 3.0 with the compound of formula III.

[0194] Pyridine can be present in any suitable ratio with the compound of formula III. For example, pyridine 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 3.2, 2.9 to 3.1 with the compound of formula III. In some embodiments, pyridine can be present in a molar ratio of 2.8 to 3.2 with the compound of formula III. Pyridine can 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 with the compound of formula III. In some embodiments, pyridine can be present in a molar ratio of about 3.0 with the compound of formula III.

[0195] 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, dimethylbenzene or a combination thereof. In certain embodiments, the third reaction mixture may also include a third solvent. In certain embodiments, the third solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dimethylbenzene or a combination thereof. In certain embodiments, the third reaction mixture may also include 2-methyltetrahydrofuran and toluene.

[0196] In some embodiments, the method of preparing a compound of Formula IIb further comprises: (c1) adding a third acid and water to the third reaction mixture to form a post-treatment mixture; and (c2) distilling the post-treatment mixture to form an intermediate mixture comprising a compound of Formula IIb.

[0197] The third acid of step (c1) can be any suitable acid. In some embodiments, the third acid comprises formic acid, acetic acid, propionic acid, butyric acid, caproic acid, caprylic acid, trifluoroacetic acid or a mixture thereof. In some embodiments, the third acid comprises acetic acid.

[0198] In some embodiments, the second reaction mixture further comprises an intermediate mixture comprising a compound of Formula lib.

[0199] In some embodiments, the method of preparing the compound of Formula IIa comprises the steps of:

[0200] (c) forming a compound comprising tetrahydrofuran, toluene, iPrMgCl, and the formula III:

[0201] and

[0202] 2-Bromo-pyridine:

[0203] The third reaction mixture

[0204] wherein the pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 3.0 to the compound of formula III;

[0205] (c1) adding acetic acid and water to the third reaction mixture to form the post-treatment mixture;

[0206] (c2) distilling the post-treatment mixture to form the intermediate mixture comprising the compound of formula IIb:

[0207] as well as

[0208] (b) forming the second reaction mixture comprising the intermediate mixture, acetonitrile and methanesulfonic acid to form the compound of Formula IIa having the structure:

[0209]

[0210] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0211]

[0212] The method comprises:

[0213] (c) forming a compound comprising tetrahydrofuran, toluene, iPrMgCl, and formula III:

[0214] and

[0215] 2-Bromo-pyridine:

[0216] The third reaction mixture,

[0217] wherein the pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of formula III;

[0218] (c1) adding acetic acid and water to the third reaction mixture to form a post-treatment mixture;

[0219] (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of Formula IIb:

[0220]

[0221] (b) forming a second reaction mixture comprising the intermediate mixture, acetonitrile and methanesulfonic acid to form a compound of Formula IIa having the structure:

[0222]

[0223] (a) forming a reaction mixture comprising the compound of formula IIa, triethylamine, ethyl acetate and 4-(trifluoromethyl)benzenesulfonyl chloride:

[0224] The first reaction mixture

[0225] wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of formula IIa;

[0226] (a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride;

[0227] (a2) adding HCl and water to the first reaction mixture to separate the first reaction mixture into a first aqueous mixture and a first organic mixture;

[0228] (a3) separating the first aqueous mixture from the first organic mixture;

[0229] (a4) concentrating the first organic mixture;

[0230] (a5) adding ethanol to the concentrated first organic mixture; and

[0231] (a6) adding water to the concentrated first organic mixture to precipitate the compound of formula I with a yield of at least 75% and a purity of at least 98%.

[0232] IV. Method for preparing formula IIB from formula III

[0233] The compound of formula IIb can be prepared by any suitable method, such as the method described for intermediate 11 of U.S. Patent No. 8,859,774. In some embodiments, the present invention provides a method for preparing a compound of formula IIb:

[0234]

[0235] The method comprises the steps of:

[0236] (c) forming a compound of formula III comprising a Grignard reagent:

[0237] and

[0238] 2-Bromo-pyridine:

[0239] The third reaction mixture,

[0240] wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of formula III, to prepare the compound of formula IIb.

[0241] 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. In some embodiments, the Grignard reagent comprises iPrMgCl.

[0242] The Grignard reagent can be present in any suitable molar ratio with 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, 2.9 to 3.1 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.8 to 3.3 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.9 to 3.2 with 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 with the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 3.0 with the compound of formula III.

[0243] Pyridine can be present in any suitable ratio with the compound of formula III. For example, pyridine 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 3.2, 2.9 to 3.1 with the compound of formula III. In some embodiments, pyridine can be present in a molar ratio of 2.8 to 3.2 with the compound of formula III. Pyridine can 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 with the compound of formula III. In some embodiments, pyridine can be present in a molar ratio of about 3.0 with the compound of formula III.

[0244] 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 certain embodiments, the third reaction mixture may also include a third solvent. In certain embodiments, the third solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene or a combination thereof. In certain embodiments, the third reaction mixture may also include tetrahydrofuran and toluene.

[0245] In some embodiments, the method of preparing a compound of Formula IIb further comprises: (c1) adding an acid and water to the third reaction mixture to form a post-treatment mixture; and (c2) distilling the post-treatment mixture to form an intermediate mixture comprising a compound of Formula IIb.

[0246] The acid of step (c1) can be any suitable acid. In some embodiments, the acid comprises formic acid, acetic acid, propionic acid, butyric acid, caproic acid, caprylic acid, trifluoroacetic acid or a mixture thereof. In some embodiments, the acid comprises acetic acid.

[0247] In some embodiments, the method of preparing a compound of Formula IIb comprises:

[0248] (c) forming a compound comprising iPrMgCl, tetrahydrofuran, toluene, and formula III:

[0249] and

[0250] 2-Bromo-pyridine:

[0251] The third reaction mixture,

[0252] wherein pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of formula III, to prepare a compound of formula IIb:

[0253]

[0254] (c1) adding acetic acid and water to the third reaction mixture to form a post-treatment mixture; and

[0255] (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIb.

[0256] V. Low-Impurity Composition

[0257] The present invention provides a composition of formula I with low impurity content. Impurity content can be expressed in a variety of different ways. For example, impurity content can be expressed as (HPLC peak area)%. In some embodiments, impurity content can be expressed as (HPLC peak area)%. In some embodiments, the present invention provides a composition comprising:

[0258] An amount of at least 99% of a compound of formula I:

[0259] and

[0260] One or more impurities in an amount of 0.01 to 1%.

[0261] The composition of Formula I may contain one or more impurities present in a total amount of 0.01% to 1%. In some embodiments, the impurities include at least one of the following:

[0262] The compound of formula XA is present in an amount less than 0.5%:

[0263]

[0264] The compound of formula XC is present in an amount less than 0.5%:

[0265]

[0266] The compound of formula X-5 in an amount less than 0.1%:

[0267] and

[0268] The compound of formula X-6 in an amount less than 0.1%:

[0269]

[0270] Impurities present in a composition of a compound of Formula I may include an amount of less than 1% of a compound of Formula XA. For example, a composition of a compound of Formula I may include less than 1.0%, 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% of a compound of Formula XA. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.5% of a compound of Formula XA. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.3% of a compound of Formula XA. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% of a compound of Formula XA.

[0271] Impurities present in the composition of the compound of formula I may include an amount of less than 1% of the compound of formula XC. For example, the composition of the compound of formula I may include less than 1.0%, 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% of the compound of formula XC. In some embodiments, the composition comprising the compound of formula I may contain less than 0.5% of the compound of formula XC. In some embodiments, the composition comprising the compound of formula I may contain less than 0.3% of the compound of formula XC. In some embodiments, the composition comprising the compound of formula I may contain less than 0.2% of the compound of formula XC. In some embodiments, the composition comprising the compound of formula I may contain less than 0.1% of the compound of formula XC. In some embodiments, the composition comprising the compound of formula I may contain less than 0.05% of the compound of formula XC.

[0272] Impurities present in a composition comprising a compound of Formula I may contain less than 1.0%, 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% of a compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.25% of a compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.2% of a compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% of a compound of Formula X-5.

[0273] Impurities present in a composition comprising a compound of Formula I may contain less than 1.0%, 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% of a compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.25% of a compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.2% of a compound of Formula X-6. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% of a compound of Formula X-6.

[0274] In some embodiments, the impurities include: a compound of formula XA in an amount less than 0.1%; a compound of formula XC in an amount less than 0.2%; a compound of formula X-5 in an amount less than 0.1%; and a compound of formula X-6 in an amount less than 0.1%.

[0275] Impurities present in a composition comprising a compound of Formula I may contain 4-(trifluoromethyl)ethyl benzenesulfonate in an amount less than 100 ppm. For example, a composition comprising a compound of Formula I may contain 4-(trifluoromethyl)ethyl benzenesulfonate impurities in an amount less than 100 ppm, or less than 90 ppm, 80 ppm, 75 ppm, 60 ppm, 50 ppm, 40 ppm, 30 ppm, or less than 25 ppm. In some embodiments, a composition comprising a compound of Formula I may contain 4-(trifluoromethyl)ethyl benzenesulfonate impurities in an amount less than 25 ppm.

[0276] Impurities present in a composition comprising a compound of Formula I may contain less than 100 ppm of 4-(trifluoromethyl)benzenesulfonyl chloride. For example, a composition comprising a compound of Formula I may contain less than 100 ppm, or less than 90 ppm, 80 ppm, 75 ppm, 60 ppm, 50 ppm, 40 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, or less than 10 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. In some embodiments, a composition comprising a compound of Formula I may contain less than 10 ppm of 4-(trifluoromethyl)benzenesulfonyl chloride.

[0277] In some embodiments, the impurities further comprise: 4-(trifluoromethyl)benzenesulfonyl chloride in an amount less than 10 ppm; and ethyl 4-(trifluoromethyl)benzenesulfonate in an amount less than 25 ppm.

[0278] In some embodiments, the composition comprising the compound of Formula I may also contain a compound of Formula XB in an amount less than 0.1%:

[0279]

[0280] In some embodiments, the composition comprising the compound of Formula I may also contain one or more of the following impurities:

[0281] The compound of formula XD is present in an amount less than 0.2%:

[0282] and

[0283] The compound of formula XE in an amount less than 0.1%:

[0284]

[0285] In some embodiments, the composition comprising the compound of Formula I may also contain a compound of Formula XH in an amount less than 0.15%:

[0286]

[0287] In some embodiments, the composition comprising the compound of Formula I may also contain one or more of the following impurities:

[0288] The compound of formula XD is present in an amount less than 0.2%:

[0289]

[0290] The compound of formula XE in an amount less than 0.1%:

[0291]

[0292] and

[0293] The compound of formula XH is present in an amount less than 0.15%:

[0294]

[0295] VI. Crystalline Form of Formula IIA

[0296] The present invention also provides a crystalline salt form of a compound of formula IIa, including but not limited to methanesulfonic acid, dibenzoyl-L-tartaric acid, 4-nitrobenzoic acid and (1S)-(+)-camphorsulfonic acid crystalline salts. In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, which is:

[0297] (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid;

[0298] (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone camphorsulfonic acid;

[0299] (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone dibenzoyl-L-tartaric acid; or

[0300] (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone 4-nitrobenzoic acid.

[0301] In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid:

[0302]

[0303] It is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 7.8° 2-θ ± 0.2° 2-θ, 14.7° 2-θ ± 0.2° 2-θ, and 15.5° 2-θ ± 0.2° 2-θ.

[0304] In some embodiments, the XRPD further includes peaks at approximately 11.6° 2-θ±0.2° 2-θ, 21.3° 2-θ±0.2° 2-θ, 22.4° 2-θ±0.2° 2-θ, and 23.2° 2-θ±0.2° 2-θ. In some embodiments, the XRPD further includes peaks at approximately 12.1°2-θ±0.2°2-θ, 14.4°2-θ±0.2°2-θ, 17.1°2-θ±0.2°2-θ, 20.4°2-θ±0.2°2-θ, 20.7°2-θ±0.2°2-θ, 20.9°2-θ±0.2°2-θ, 22.4°2-θ±0.2°2-θ, 26.2°2-θ±0.2°2-θ, 26.8°2-θ±0.2°2-θ, and 27.6°2-θ±0.2°2-θ. In some embodiments, the XRPD further comprises peaks at about 7.8° 2-θ ± 0.2° 2θ, 11.6° 2-θ ± 0.2° 2θ, 12.1° 2-θ ± 0.2° 2θ, 14.4° 2-θ ± 0.2° 2θ, 14.7° 2-θ ± 0.2° 2θ, 15.5° 2-θ ± 0.2° 2θ, 17.1° 2-θ ± 0.2° 2θ, 20.4° 2-θ ± 0.2° 2θ, 2θ, 20.7°2-θ±0.2°2θ, 20.9°2-θ±0.2°2θ, 21.3°2-θ±0.2°2θ, 22.4°2-θ±0.2°2θ, 23.2°2-θ±0.2°2θ, 26.2°2-θ±0.2°2θ, 26.8°2-θ±0.2°2θ, and 27.6°2-θ±0.2°2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern substantially as shown in Table 2. In some embodiments, the crystalline form is characterized by an XRPD pattern substantially as shown in Table 2. Figure 2 as shown in .

[0305] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 191° C. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram substantially as Figure 3 as shown in .

[0306] In some embodiments, the crystalline form is characterized by thermogravimetric analysis (TGA) substantially as follows Figure 4 as shown in .

[0307] In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone camphorsulfonic acid. In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone dibenzoyl-L-tartaric acid. In some embodiments, the present invention provides a crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone 4-nitrobenzoic acid.

[0308] VII. Composition

[0309] In some embodiments, the present invention provides a pharmaceutical composition comprising the low impurity composition of the present invention and a pharmaceutically acceptable excipient.

[0310] The low-impurity composition of the present invention can be prepared and applied in various oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for patient intake. The low-impurity composition of the present invention can also be applied by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal administration. In addition, the compounds described herein can be applied by inhalation, such as nasal administration. In addition, the low-impurity composition of the present invention can be applied transdermally. The compound of formula I of the present invention can also be applied by intraocular, intravaginal and intrarectal routes (including suppositories, insufflations, powders and aerosol preparations) (e.g., steroid inhalers, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995). Therefore, the present invention also provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and / or excipients and a compound of formula I.

[0311] For preparing pharmaceutical compositions from the low impurity compositions of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible particles. Solid carriers can be one or more substances that can also be used as diluents, flavoring agents, adhesives, preservatives, tablet disintegrants, or encapsulating materials. Technical details about formulations and administration are well described in the scientific and patent literature, see, for example, the latest version of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0312] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties and additional excipients as required in suitable proportions and compacted in the desired shape and size.

[0313] Powders, capsules and tablets preferably contain 5% or 10% to 70% of active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc. The term "preparation" is intended to include preparations of active compounds with encapsulating materials as carriers, which provide capsules in which the active components with or without other excipients are surrounded by the carrier and thereby combined with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0314] Suitable solid excipients are carbohydrate or protein fillers, including but not limited to sugars, including lactose, sucrose, mannitol or sorbitol; Starch from corn, wheat, rice, potato or other plants; Cellulose, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen. If necessary, disintegrating agents or solubilizing agents, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, can be added.

[0315] The dragee core is provided with a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or dragee coating for product identification or characterization of the amount (i.e., dosage) of the active compound. The pharmaceutical preparation of the present invention may also be used orally in push-fit capsules, such as made of gelatin, and soft sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain a compound of formula I mixed with a filler or adhesive (such as lactose or starch), a lubricant (such as talc or magnesium stearate), and an optional stabilizer. In a soft capsule, the compound of formula I may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol with or without a stabilizer.

[0316] To prepare 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 uniformly therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0317] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0318] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may also contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc. in addition to the active ingredient.

[0319] Oil suspensions can be prepared by suspending the compound of formula I in vegetable oils (such as peanut oil, olive oil, sesame oil or coconut oil) or mineral oils (such as liquid paraffin) or mixtures thereof. Oil suspensions can contain thickeners, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These preparations can be preserved by adding antioxidants such as ascorbic acid. As an example of an oil vehicle for injection, see Minto, J.Pharmacol.Exp.Ther.281:93-102,1997. The pharmaceutical preparations of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil or a mixture thereof as described above. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth; naturally occurring phospholipids such as soy 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 flavorings, such as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, a preservative, or a coloring agent.

[0320] The low impurity compositions of the present invention can be delivered transdermally via a topical route and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0321] The low impurity composition of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered via intradermal injection of drug-containing microspheres for slow release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as a biodegradable and injectable gel formulation (see, e.g., Gao Pharm. Res. 12: 857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). Both transdermal and intradermal routes provide sustained delivery for weeks or months.

[0322] In some embodiments, the formulation of the low impurity composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, that is, by using a ligand attached to the liposome or directly attached to the oligonucleotide, which binds to the cell surface membrane protein receptor to cause endocytosis. By using liposomes, especially when the liposome surface carries a ligand specific to the target cell or otherwise preferentially targets a specific organ, the GR modulator can be delivered to the target cell in vivo. (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).

[0323] The pharmaceutical formulations are preferably in unit dosage form. In such form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Likewise, the unit dosage form itself can be a capsule, tablet, cachet, or lozenge, or can be an appropriate number of any of these in packaged form.

[0324] The amount of active ingredient in a unit dose formulation can vary or be adjusted between 0.1 mg and 10000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 mg to 500 mg, depending on the specific application and the effectiveness of the active ingredient. For example, the dosage can be 50 mg or 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. If desired, the composition can also contain other compatible therapeutic agents.

[0325] The dosing regimen also takes into account pharmacokinetic parameters well known in the art, i.e., absorption rate, 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; the latest Remington's, supra). The existing technology allows the clinician to determine the dosing regimen for each individual patient, GR and / or MR modulator, and disease or condition being treated.

[0326] The single or multiple administration of the preparation can be applied according to the dosage and frequency required and tolerated by the patient. The preparation should provide a sufficient amount of active agent to effectively treat the disease state. Therefore, in one embodiment, the daily amount of the pharmaceutical preparation for oral administration of the low-impurity composition is between about 0.5 mg and about 30 mg per kilogram of body weight per day. In an alternative embodiment, a dosage of about 1 mg to about 20 mg per kg of body weight per day per patient is used. Compared with oral administration, a lower dose can be used, especially when the drug is applied to an anatomically hidden part (such as cerebrospinal fluid (CSF) space), enters the bloodstream, enters the body cavity or enters the lumen of an organ. Significantly higher doses can be used in local administration. The actual method for preparing a preparation of a compound comprising Formula I for parenteral administration is known or obvious to those skilled in the art, and is described in more detail in publications such as Remington's as described above. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal et al., eds., De Gruyter, New York (1987).

[0327] The low impurity compositions described herein can be used in combination with each other, with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjunct agents that may not be effective alone but may aid in the efficacy of the active agent.

[0328] In some embodiments, co-administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration comprises administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition comprising two active agents. In some embodiments, active agents can be formulated separately. In some embodiments, active agents and / or adjuvants can be connected or conjugated to each other.

[0329] After the pharmaceutical composition comprising the compound of formula I of the present invention is formulated in one or more acceptable carriers, it can be placed in an appropriate container and labeled to treat a specified condition. For the administration of the compound of formula I, such labeling will include, for example, instructions on the amount, frequency and method of administration.

[0330] In certain embodiments, the low impurity composition of the present invention can be used for parenteral administration, such as intravenous (IV) administration or administration to a body cavity or organ lumen. The preparation for administration will generally include a solution of the composition of the present invention dissolved in one or more pharmaceutically acceptable carriers. In addition, sterile fixed oils can be conventionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections. These solutions are sterile and generally do not contain unwanted substances. These preparations can be sterilized by conventional well-known sterilization techniques. The preparation can contain pharmaceutically acceptable auxiliary substances required for close physiological conditions, such as pH regulators and buffers, tension regulators, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these preparations can vary over a wide range, and will be selected mainly according to fluid volume, viscosity, body weight, etc., according to the selected specific mode of administration and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0331] VIII. Methods and Uses

[0332] In some embodiments, the present invention provides a method of treating a disorder or condition by modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the low impurity compositions of the present invention or the pharmaceutical compositions of the present invention, thereby treating the disorder or condition.

[0333] In some embodiments, the present invention provides a method of treating a disorder or condition by antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment an effective amount of any of the low impurity compositions of the present invention or the pharmaceutical compositions of the present invention.

[0334] 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, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by excess cortisol associated with adrenal disease, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical fractures, GR-related metabolic disorders, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and nervous system disorders in premature infants.

[0335] In certain embodiments, the method comprises administering one or more second medicaments (e.g., therapeutic agents). In certain embodiments, the method comprises administering one or more second medicaments (e.g., therapeutic agents) of therapeutically effective amount. In certain embodiments, the second medicament is a medicament known to be used for regulating glucocorticoid receptors. In certain embodiments, the second medicament is a medicament for treating amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorder caused by excessive cortisol associated with adrenal disease, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, postoperative fracture, GR-related metabolic disorder, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorder, weight gain caused by antipsychotics, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression and the medicament of the nervous system disorder of premature infants. In some embodiments, the second agent is an agent used to treat major psychotic depression, stress disorder, or antipsychotic-induced weight gain. In some embodiments, the second agent is an agent used to treat nonalcoholic fatty liver disease and / or nonalcoholic steatohepatitis. In some embodiments, the second agent is an agent used to treat an addiction disorder. In some embodiments, the second agent is an agent used to treat cancer. In some embodiments, the second agent is an anticancer agent. In some embodiments, the second agent is a chemotherapeutic agent.

[0336] In some embodiments, any of the low impurity compositions of the invention or the pharmaceutical compositions of the invention may be used in a method of treating a disorder or condition by modulating the glucocorticoid receptor.

[0337] In some embodiments, any of the low impurity compositions of the invention or the pharmaceutical compositions of the invention may be used in a method of treating a disorder or condition by antagonizing a glucocorticoid receptor.

[0338] In some embodiments, any of the low impurity compositions of the invention or the pharmaceutical compositions of the invention can be used in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0339] In some embodiments, any of the low impurity compositions of the invention or the pharmaceutical compositions of the invention can be used in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0340] In some embodiments, the present invention provides a method for treating amyotrophic lateral sclerosis (ALS), comprising administering a therapeutically effective amount of a low impurity composition of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof, thereby treating fatty liver disease.

[0341] In some embodiments, any of the low impurity compositions of the invention or the pharmaceutical compositions of the invention can be used to manufacture a medicament for treating amyotrophic lateral sclerosis (ALS).

[0342] IX. Examples

[0343] The following abbreviations are used in the following methods:

[0344] ℃ Celsius ACN、MeCN Acetonitrile aq Water-based atm Atmospheric pressure Barg Bar(g); gauge pressure in bar Boc tert-Butyloxycarbonyl DIPEA <![CDATA[N,N-Diisopropylethylamine (iPr2NEt)]]> EtOAc Ethyl acetate eq or equiv equivalent FA Formic acid g gram HDPE High Density Polyethylene Kg kilogram L Lift M Moore mbar millibar mins minute mL ml MSA Methanesulfonic acid MTBE Methyl tert-butyl ether nm nanometer NMR Nuclear Magnetic Resonance share PMI Potentially mutagenic impurities ppm Parts per million r.t. Room temperature THF Tetrahydrofuran μm Micrometer

[0345] X-ray powder 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 in transmission mode and held between low-density polyethylene films. The XRPD program used contained the following parameters: (1) range 3-40° 2θ, (2) step size 0.013°, (3) counting time 99 seconds, and (4) approximately 22 minutes run time. XRPD patterns were sorted using HighScore Plus 2.2c software.

[0346] Differential Scanning Calorimetry (DSC). DSC analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. Accurately weighed samples were placed in crimped aluminum pans. Each sample was heated to a maximum of 300°C at a rate of 10°C / min under nitrogen. Indium metal was used as a calibration standard. The temperature was reported to the nearest 0.01 degree at the beginning of the transition.

[0347] The reaction step of the present invention can be carried out for any suitable reaction time. For example, the reaction time can last for several minutes, hours or days. In some embodiments, the reaction time can last for several hours, such as at least eight hours. In some embodiments, the reaction time can last for several hours, such as at least overnight. In some embodiments, the reaction time can last for several days. In some embodiments, the reaction time can last for at least two hours. In some embodiments, the reaction time can last for at least eight hours. In some embodiments, the reaction time can last for at least several days. In some embodiments, the reaction time can last for about two 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 last for about 1 day, or about two days, or about three days, or about four days, or about five days, or about six days, or about one week, or about more than one week.

[0348] The reaction steps of the present invention can be carried out at any suitable reaction temperature. Representative temperatures include but are not limited to below room temperature, at room temperature or above room temperature. Other temperatures that can be used in the method 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 at a temperature of about 15 ° C, or at about 20 ° C, or at about 25 ° C, or at about 30 ° C, or at about 35 ° C, or at about 40 ° C, or at about 45 ° C, or at about 50 ° C, or at about 55 ° C, or at about 60 ° C, or at about 65 ° C.

[0349] Example 1. (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexa Preparation of Hydrogen-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

[0350]

[0351] Two 400 L containers (A and B) were boiled with ethyl acetate before use. Container A was used for the reaction, and container B was equipped with an in-line filter and used to precipitate dazoclidine (CORT113176). COR176-2 [15.692 kg, (11.948 kg, 31.91 moles (corrected))] and ethyl acetate [213.8 kg, 235 L, 15 vol] were added to container A. The contents were stirred for 5 minutes and then cooled to 0°C.

[0352] Anhydrous triethylamine [6.81 kg, 67.30 moles, 2.1 eq] was added to Vessel A over 17 minutes while maintaining the batch temperature below 10° C. The contents of Vessel A were aged at 0° C. for 51 minutes.

[0353] To vessel A was added 4-(trifluoromethyl)benzenesulfonyl chloride [7.960 kg, 32.54 moles, 1 eq.] in ethyl acetate [27.4 kg, 31.4 L, 2 vol.] over 40 minutes while maintaining the batch temperature below 10° C. The batch was aged at 0° C. for 2 hours and then analyzed for conversion of COR176-2 to dazoclinic.

[0354] N-methylpiperazine [0.808 kg, 8.07 moles, 25 mol %] was added to vessel A. The batch was warmed to 20°C and aged for 3 hours.

[0355] Hydrochloric acid solution [0.5 M; 79 kg, 5 vols.] was added to vessel A at 20°C and the contents were aged for 10 minutes. The aqueous layer was discarded, the organic layer was washed again with hydrochloric acid solution [0.5 M; 79 kg, 5 vols.], the contents were aged for at least 10 minutes, and the aqueous layer was discarded.

[0356] Purified water [79 kg, 5 vols.] was added to the vessel, the organics were washed for at least 10 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. This step was repeated twice.

[0357] The solution of dazoclirine was drained into a vat and analyzed by HPLC for assay yield (for monitoring purposes only). 1-Methyl-4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine was not observed in the assay yield HPLC trace (<0.04A%).

[0358] Vessel B, which had the oyster filter and API hose as part of it, was tested for foreign matter using ethyl acetate from the initial boil. This was to ensure that solid contamination of the final API did not occur.

[0359] The dazoclinic solution was transferred to vessel B via a 1 micron in-line filter cartridge. The organic stream was concentrated from approximately 260 L to 31 L [2 vol] under reduced pressure while maintaining the batch temperature below 45° C. Ethanol [150 kg, 12 vol] was added to vessel B via a 1 micron in-line filter cartridge. The solution was then concentrated from approximately 220 L to 47 L [3 vol] under reduced pressure while maintaining the batch temperature below 45° C. The dazoclinic solution was cooled to 20° C. and then analyzed by GC for ethyl acetate content.

[0360] Transfer the dazocline solution to a clean plastic lined vat [50 kg]. Add ethanol [15.7 kg, 1.25 vols.] to container B via a 1 micron inline filter cartridge, stir the contents for 5 minutes and combine with the dazocline solution. Add ethanol [50 kg, 3 vols.] to container B via a 1 micron inline filter cartridge, stir the contents and then discard into a vat for disposal. Add purified water [236 kg, 15 vols.] to container B via a 1 micron inline filter cartridge. Add the dazocline solution to container B at a stirring speed of 170 rpm for 38 minutes. Age the contents of container B for 12 hours and then analyze the liquid for liquid loss (for reference only).

[0361] The slurry was filtered and the filter cake was washed with purified water [47 kg, 3 vol]. The solid was dried under a nitrogen stream for 5 hours and then dried in a vacuum oven at 60°C for 64 hours. 18.46 kg (99.3% relative to COR176-2) of dazoclinic as a white solid.

[0362] Table 1: Comparison of analytical data for batches measured by API release method

[0363]

[0364] The characterization data of the title compound are consistent with those of Example 1 of US Patent No. 8,859,774.

[0365] Example 2. (R)-1-(4-Fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4- Preparation of g]isoquinolin-6-ium methanesulfonate

[0366]

[0367] Method A

[0368] The 400 L vessel was rinsed with toluene before use. COR176-1 [21.04 kg, 44.3 mol, 1.0 eq] was concentrated as a stream in toluene [259.8 kg] to 42 L [2 vol] under reduced pressure while maintaining the batch temperature below 45 °C.

[0369] MeCN [166.1 kg] was added and the batch was concentrated from approximately 200 L to 42 L [2 vol] under reduced pressure while maintaining the batch temperature below 45° C. MeCN [27.0 kg] was added and a sample was taken to measure the toluene content by GC.

[0370] The batch was cooled to 9.7° C. and MSA [17.14 kg, 178.3 mol, 4.0 eq] was added over 1 hour while maintaining the internal batch temperature below 15° C. The batch was aged at 23-24° C. for 16 hours and then sampled to measure reaction conversion by HPLC.

[0371] The batch was cooled to 9°C and Et3N [9.47 kg, 93.6 mol, 2.1 eq.] was added over 25 minutes while maintaining the internal temperature below 15°C.

[0372] The batch was seeded with a slurry of COR176-2 (102 g, 0.2 mol, 0.5 mol%) in MeCN [300 g] and aged at 16°C for 30 min.

[0373] Et3N [3.06 kg, 30.2 mol, 0.68 eq.] was added over 30 minutes while maintaining the internal temperature below 20° C. The batch was aged at 23° C. for 1 hour and then ethyl acetate [114 kg, 6 vols.] was added over 20 minutes. The batch was cooled to -19.7° C. for at least 2 hours after which a sample was taken to measure liquid loss by HPLC.

[0374] The batch was filtered and then washed twice with THF [46.8 kg, 2.5 vols and 37.1 kg, 2 vols] and dried under a stream of nitrogen for 1 hour. The filter cake was dried at 40° C. under vacuum with a minimal nitrogen purge for 14 hours and analyzed for weight percentage. 15.81 kg of isolated COR176-2 was obtained (76.14 wt % COR176-2 (free base) in the salt, corresponding to 73% isolated yield).

[0375] Method B

[0376] To a 3 L round bottom flask was added 2151.22 g of COR176-1 in toluene [8.9% COR176-1, 191.46 g COR176-1]. The mixture was concentrated to 380 mL [2 vol] under reduced pressure while maintaining the batch temperature below 45°C.

[0377] MeCN [1493 g, 1900 mL] was added and the mixture was concentrated to 380 mL [2 vol] under reduced pressure while maintaining the batch temperature below 45° C. MeCN [239 g, 304 mL, 1.6 vol] was added and a sample was taken to measure the toluene content by GC. The mixture was transferred to a 2 L Radleys reactor under a nitrogen purge and cooled to 10° C.

[0378] Methanesulfonic acid [155 g, 105 mL, 4.0 eq.] was added over 1 hour while maintaining the internal temperature of the batch below 15° C. The batch was aged at 22° C. for 14 hours and then sampled to measure the reaction conversion by HPLC.

[0379] The batch was cooled to 10°C and Et3N [85 g, 117 mL, 2.1 eq.] was added over at least 30 min while maintaining the internal temperature below 15°C.

[0380] The batch was seeded with a slurry of COR176-2 (0.94 g, 0.5 mol%) and aged at 15°C for 30 minutes.

[0381] Et3N [28 g, 38 mL, 0.68 eq.] was added over 30 minutes while maintaining the internal temperature below 20° C. The batch was aged at 20° C. for 1 hour and then ethyl acetate [1028 g, 1140 mL, 6 vols.] was added over 20 minutes. The batch was cooled to -20° C. for at least 2 hours after which a sample was taken to measure liquid loss by HPLC.

[0382] The batch was filtered and then washed twice with THF [425 g, 475 mL, 2.5 vols and 338 g, 380 mL, 2 vols] and dried under a stream of nitrogen for 1 hour. The filter cake was dried at 40° C. under vacuum with minimal nitrogen purge for 12 hours and analyzed for weight percent. 149.12 g of isolated COR176-2 was obtained (79% isolated yield).

[0383] Table 2. XRPD peaks of the crystalline form of (R)-1-(4-fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium methanesulfonate

[0384]

[0385]

[0386] Example 3. (R)-1-(4-Fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4- g] Preparation of isoquinolin-6-ium salt

[0387]

[0388] An additional crystalline acid salt of (R)-1-(4-fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium was prepared using dibenzoyl-L-tartaric acid, 4-nitrobenzoic acid, and (1S)-(+)-camphorsulfonic acid.

[0389] Example 4. (R)-1-(4-Fluorophenyl)-4a-picolinoyl-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4- g] Preparation of tert-butyl isoquinoline-6-carboxylate

[0390]

[0391] Before use, a 1000L container was boiled with toluene. Compound 9 can be prepared according to Example 33 of U.S. Patent No. 7,928,237. Compound 9 [19.48kg, 45.6mol, 1.0eq] and toluene [84.6kg, 97L, 5vols.] were added to the container. The solid was then dissolved at 19°C for 5 minutes, and the resulting solution was degassed three times under the positive pressure of nitrogen (the container was pressurized to 1000 bar and vented to atmospheric pressure). The solution of compound 9 was transferred to a clean plastic-lined vat. The container was rinsed with toluene [67.6kg, 78L, 4vols.] and then merged with the compound 9 solution.

[0392] The vessel was charged with 2-bromopyridine [21.84 kg, 138.2 mol, 3.0 eq] and toluene [168.8 kg, 195 L, 10 vols.] The 2-bromopyridine solution was degassed three times under a positive pressure of nitrogen (vessel was pressurized to 1000 bar and vented to atmospheric pressure).

[0393] Approximately 20% isopropylmagnesium chloride in THF [68.4 kg, 137.0 mol, 3.0 eq] was added to the vessel over 75 minutes while maintaining the batch temperature below 22° C. The resulting mixture was aged at 24° C. for 16.5 hours.

[0394] The solution of Compound 9 was added to the vessel over 37 minutes while maintaining the batch temperature below 22° C. The batch was aged for 1 hour and then analyzed by HPLC for conversion of Compound 9 (for monitoring purposes only). The reaction was aged at 22° C. for a total of 2 hours.

[0395] The batch was cooled to 12° C. and acetic acid [27.69 kg, 461.1 mol, 10.0 eq] was added over 1 hour while maintaining the batch temperature below 22° C. The quenched mixture was aged for 17.75 hours before sampling to monitor the reaction profile by HPLC (for monitoring purposes only).

[0396] Add 1M hydrochloric acid solution [199 kg, 195 L, 10 vols.] to the container, age for 15 minutes, allow the two-phase mixture to settle, and drain the water layer. Repeat this step once more. Add purified water [199 kg, 195 L, 10 vols.] to the container, age for 15 minutes, allow the two-phase mixture to settle, and drain the water layer. Repeat this step once more.

[0397] The organic stream was concentrated from approximately 420 L to 293 L [15 vol] under reduced pressure while maintaining the batch temperature below 45° C. The organic stream was cooled to 20° C. and transferred to a clean plastic lined drum. The solution was sampled and analyzed for weight percent (calculated as 8.1 wt % - 21.34 kg in 263.4 kg crude solution (98.7% test yield)).

[0398] The characterization data of the title compound were consistent with those of Intermediate 11 of US Pat. No. 8,859,774.

[0399] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were incorporated by reference individually. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof: The method comprises: (a) forming a compound comprising formula II: 4-(Trifluoromethyl)benzenesulfonyl chloride: to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%, in HX is an acid solvate; and The subscript n is 1 to 4.

2. The method according to claim 1, wherein HX in R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl or 3. The method according to claim 1 or 2, wherein HX in R 1 C 1-6 Alkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl or 4. The method according to any one of claims 1 to 3, wherein HX is MeS(O)2OH, 5. The process according to any one of claims 1 to 4, wherein HX is MeS(O)2OH.

6. The method according to claim 1 or 2, comprising: (a) forming a compound comprising formula IIa: and 4-(Trifluoromethyl)benzenesulfonyl chloride: to produce the compound of formula I with a yield of at least 60% and a purity of at least 98%, in R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and The subscript n is 1 to 4.

7. The process of claim 6, wherein the compound of formula I is prepared in a yield of at least 75% and a purity of at least 98%.

8. The method according to claim 6 or 7, wherein R 1 C 1-2 Alkyl, C 1-2 Haloalkyl, phenyl or 4-methylphenyl.

9. The method according to any one of claims 6 to 8, wherein R 1 It is methyl, ethyl, -CF3, phenyl or 4-methylphenyl.

10. The method according to any one of claims 6 to 9, wherein R 1 It is methyl.

11. The method according to any one of claims 6 to 10, wherein n is 1.

12. The method of any one of claims 1 to 11, wherein the first reaction mixture further comprises a non-nucleophilic amine base.

13. The method of claim 12, 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-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof.

14. The method of claim 12 or 13, wherein the non-nucleophilic amine base comprises triethylamine.

15. The method of any one of claims 1 to 14, wherein the first reaction mixture further comprises a first solvent.

16. The method of claim 15, wherein the first solvent comprises ethyl acetate, isopropyl acetate or n-butyl acetate or a mixture thereof.

17. The method of claim 15 or 16, wherein the first solvent comprises ethyl acetate.

18. The method of any one of claims 6 to 17, wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of formula IIa.

19. The method according to any one of claims 1 to 18, further comprising the steps of: (a1) adding an amino group scavenger to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride.

20. The method of claim 19, wherein the amino scavenger comprises N-methylpiperazine, N 1 ,N 1 -Dimethylethane-1,2-diamine, N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine or N 1 ,N 1 -Bis(2-aminoethyl)ethane-1,2-diamine.

21. The method of claim 19 or 20, wherein the amino scavenger comprises N-methylpiperazine.

22. The method of any one of claims 19 to 21, wherein the amino scavenger is present in a molar ratio to the compound of formula IIa of about 0.

25.

23. The method according to any one of claims 19 to 22, further comprising the steps of: (a2) adding a first acid and water to the first reaction mixture to separate the first reaction mixture into a first aqueous mixture and a first organic mixture; and (a3) separating the first aqueous mixture from the first organic mixture.

24. The method of claim 23, wherein the first acid comprises hydrochloric acid.

25. The method according to claim 23 or 24, further comprising the steps of: (a4) concentrating the first organic mixture; (a5) adding ethanol to the concentrated first organic mixture; and (a6) adding water to the concentrated first organic mixture to precipitate the compound of formula I.

26. The method according to any one of claims 1 to 25, comprising the steps of: (a) forming a compound of formula IIa having the structure: Triethylamine, ethyl acetate and 4-(trifluoromethyl)benzenesulfonyl chloride: the first reaction mixture, wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of formula IIa; (a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride; (a2) adding HCl and water to the first reaction mixture to separate the first reaction mixture into the first aqueous mixture and the first organic mixture; (a3) separating the first aqueous mixture from the first organic mixture; (a4) concentrating the first organic mixture; (a5) adding ethanol to the concentrated first organic mixture; as well as (a6) adding water to the concentrated first organic mixture to precipitate the compound of formula I with a yield of at least 75% and a purity of at least 98%.

27. The method according to any one of claims 1 to 26, wherein the compound of formula I contains less than 1% of the compound of formula X-5:

28. A method for preparing a compound of formula IIa: The method comprises: (b) forming a compound comprising Formula IIb: and Sulfonic acid of the formula: A second reaction mixture, To form the compound of formula IIa, in R 1 C 1-6 Alkyl, C 1-10 haloalkyl, phenyl or 4-methylphenyl; and The subscript n is 1 to 4.

29. The method of claim 28, wherein the second reaction mixture further comprises a second solvent.

30. The method of claim 29, wherein the second solvent comprises acetonitrile, cyclopentyl methyl ether (CPME), tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, ethanol, diethyl ether, methyl tert-butyl ether (MTBE), toluene, or a combination thereof.

31. The method of claim 29 or 30, wherein the second solvent comprises acetonitrile.

32. The method according to any one of claims 28 to 31, wherein the compound of formula IIb is prepared by the following steps: (c) forming a compound of formula III comprising a Grignard reagent: and 2-Bromo-pyridine: The third reaction mixture, wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of formula III, to prepare the compound of formula IIb.

33. The method of claim 32, wherein the Grignard reagent comprises iPrMgCl or iPrMgBr.

34. The method of claim 32 or 33, wherein the Grignard reagent comprises iPrMgCl.

35. The method of any one of claims 32 to 34, wherein the third reaction mixture further comprises a third solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene.

36. The method of claim 35, wherein the third solvent comprises tetrahydrofuran and toluene.

37. The method according to any one of claims 32 or 36, further comprising: (c1) adding a third acid and water to the third reaction mixture to form a post-treatment mixture; as well as (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIb.

38. The method of claim 37, wherein the third acid comprises formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or a mixture thereof.

39. The method of 37 or 38, wherein the third acid comprises acetic acid.

40. The method of any one of claims 37 to 39, wherein the second reaction mixture further comprises the intermediate mixture, the intermediate mixture comprising the compound of formula lib.

41. A method according to any one of claims 32 to 40, comprising the steps of: (c) forming a compound comprising tetrahydrofuran, toluene, iPrMgCl, and the formula III: and 2-Bromo-pyridine: the third reaction mixture, wherein the pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of formula III; (c1) adding acetic acid and water to the third reaction mixture to form the post-treatment mixture; (c2) distilling the post-treatment mixture to form the intermediate mixture comprising the compound of formula IIb: as well as (b) forming the second reaction mixture comprising the intermediate mixture, acetonitrile and methanesulfonic acid to form the compound of Formula IIa having the structure:

42. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof: The method comprises: (c) forming a compound comprising tetrahydrofuran, toluene, iPrMgCl, and formula III: and 2-Bromo-pyridine: The third reaction mixture, wherein the pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of formula III; (c1) adding acetic acid and water to the third reaction mixture to form a post-treatment mixture; (c2) distilling the work-up mixture to form an intermediate mixture comprising a compound of Formula IIb: (b) forming a second reaction mixture comprising the intermediate mixture, acetonitrile and methanesulfonic acid to form a compound of Formula IIa having the structure: (a) forming a reaction mixture comprising the compound of formula IIa, triethylamine, ethyl acetate and 4-(trifluoromethyl)benzenesulfonyl chloride: The first reaction mixture wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of formula IIa; (a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride; (a2) adding HCl and water to the first reaction mixture to separate the first reaction mixture into a first aqueous mixture and a first organic mixture; (a3) separating the first aqueous mixture from the first organic mixture; (a4) concentrating the first organic mixture; (a5) adding ethanol to the concentrated first organic mixture; as well as (a6) adding water to the concentrated first organic mixture to precipitate the compound of formula I with a yield of at least 75% and a purity of at least 98%.

43. A method for preparing a compound of formula IIb: The method comprises the steps of: (c) forming a compound of formula III comprising a Grignard reagent: and 2-Bromo-pyridine: The third reaction mixture, wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of formula III, to prepare the compound of formula IIb.

44. The method of claim 43, wherein the Grignard reagent comprises iPrMgCl or iPrMgBr.

45. The method of claim 43 or 44, wherein the Grignard reagent comprises iPrMgCl.

46. ​​The method of any one of claims 43 to 45, wherein the third reaction mixture further comprises a third solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene.

47. The method of claim 46, wherein the third solvent comprises tetrahydrofuran and toluene.

48. The method of claim 47, further comprising (c1) adding an acid and water to the third reaction mixture to form a post-treatment mixture; and (c2) distilling the work-up mixture to form an intermediate mixture comprising the compound of Formula IIb.

49. The method of claim 48, wherein the acid comprises formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or mixtures thereof.

50. The method of claim 48 or 49, wherein the acid comprises acetic acid.

51. A composition comprising: An amount of at least 99% of a compound of formula I: and One or more impurities in an amount of 0.01 to 1%.

52. The composition of claim 51, wherein the impurities comprise at least one of: The compound of formula XA is present in an amount less than 0.5%: The compound of formula XC is present in an amount less than 0.5%: The compound of formula X-5 in an amount less than 0.1%: and The compound of formula X-6 in an amount less than 0.1%:

53. The composition of claim 51 or 52, wherein the impurities comprise: An amount of less than 0.1% of the compound of formula XA; An amount of less than 0.2% of the compound of formula XC; An amount of less than 0.1% of the compound of formula X-5; and The amount of the compound of formula X-6 is less than 0.1%.

54. The composition of any one of claims 51 to 53, wherein the impurities further comprise: 4-(trifluoromethyl)benzenesulfonyl chloride in an amount less than 10 ppm; and The amount was less than 25 ppm of ethyl 4-(trifluoromethyl)benzenesulfonate.

55. The composition of any one of claims 51 to 54, wherein the impurities further comprise at least one of: The compound of formula XD is present in an amount less than 0.2%: and The compound of formula XE in an amount less than 0.1%: and The compound of formula XH is present in an amount less than 0.15%:

56. A crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, which is: (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid; (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone camphorsulfonic acid; (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone dibenzoyl-L-tartaric acid; or (R)-(1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone 4-nitrophenol.

57. A crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid: Features The X-ray powder diffraction (XRPD) pattern has peaks at about 7.8° 2-θ ± 0.2° 2-θ, 14.7° 2-θ ± 0.2° 2-θ, and 15.5° 2-θ ± 0.2° 2-θ.

58. The crystalline form of claim 57, wherein the XRPD further comprises peaks at approximately 11.6° 2-θ ± 0.2° 2-θ, 21.3° 2-θ ± 0.2° 2-θ, 22.4° 2-θ ± 0.2° 2-θ, and 23.2° 2-θ ± 0.2° 2-θ.

59. The crystalline form of claim 57 or 58, wherein the XRPD further comprises peaks at approximately 12.1°2-θ±0.2°2-θ, 14.4°2-θ±0.2°2-θ, 17.1°2-θ±0.2°2-θ, 20.4°2-θ±0.2°2-θ, 20.7°2-θ±0.2°2-θ, 20.9°2-θ±0.2°2-θ, 22.4°2-θ±0.2°2-θ, 26.2°2-θ±0.2°2-θ, 26.8°2-θ±0.2°2-θ, and 27.6°2-θ±0.2°2-θ.

60. The crystalline form of any one of claims 57 to 59, wherein the XRPD comprises a value of about 7.8° 2-θ ± 0.2° 2-θ, 11.6° 2-θ ± 0.2° 2-θ, 12.1° 2-θ ± 0.2° 2-θ, 14.4° 2-θ ± 0.2° 2-θ, 14.7° 2-θ ± 0.2° 2-θ, 15.5° 2-θ ± 0.2° 2-θ, 17.1° 2-θ ± 0.2° 2-θ, 2 0.4°2-θ±0.2°2-θ, 20.7°2-θ±0.2°2-θ, 20.9°2-θ±0.2°2-θ, 21.3°2-θ±0.2°2-θ, 22.4°2-θ±0 Peaks at .2°2-θ, 23.2°2-θ±0.2°2-θ, 26.2°2-θ±0.2°2-θ, 26.8°2-θ±0.2°2-θ, and 27.6°2-θ±0.2°2-θ.

61. The crystalline form according to any one of claims 57 to 60, characterized in that The XRPD pattern is substantially as shown in FIG2 .

62. The crystalline form according to any one of claims 57 to 61, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm with an onset at about 191 °C.

63. The crystalline form according to any one of claims 57 to 62, characterized in that The differential scanning calorimetry (DSC) thermogram is substantially as shown in FIG3 .

64. The crystalline form according to any one of claims 57 to 63, characterized in that Thermogravimetric analysis (TGA) was substantially as shown in FIG4 .

65. A pharmaceutical composition comprising a composition according to any one of claims 51 to 64 and one or more pharmaceutically acceptable excipients.

66. The pharmaceutical composition of claim 65, further comprising one or more additional therapeutic agents.

67. A method for treating an obstacle or condition by regulating a glucocorticoid receptor, the method comprising administering a therapeutically effective amount of a composition according to any one of claims 51 to 55 or a pharmaceutical composition according to claim 65 or 66 to a subject in need of such treatment, thereby treating the obstacle or condition.

68. A method for treating an obstacle or condition by antagonizing a glucocorticoid receptor, the method comprising administering a therapeutically effective amount of a composition according to any one of claims 51 to 55 or a pharmaceutical composition according to claim 65 or 66 to a subject in need of such treatment, thereby treating the obstacle or condition.

69. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to any one of claims 51 to 55 or a pharmaceutical composition according to claim 65 or 66, thereby treating ALS.

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