Method for preparing a heteroaryl-ketone condensed azadecalin glucocorticoid receptor regulator

Abstract

The present invention provides a heteroaryl-ketone condensed azadecalin glucocorticoid receptor modulator and a method for preparing a composition having a low impurity concentration.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 367,151, filed on June 28, 2022, the entire contents of which are hereby incorporated herein by reference for all purposes.

Background Art

[0002] Receptors with high affinity for corticosteroids are of two types: 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 both circadian rhythm changes and increases in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid and acts by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: the ligand - binding GR - alpha of 777 amino acids and the GR - beta isoform lacking 50 carboxy - terminal residues. Since these contain a ligand - binding domain, GR - beta cannot bind ligands, is constitutively localized in the nucleus, and is transcriptionally inactive. GR is also known as GR - II.

[0003] The biological effects of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of agents can block the physiological effects of GR-agonist binding. These antagonists include compositions that bind to the GR and inhibit the ability of agonists to effectively bind to and / or activate the GR. Mifepristone, one such known GR antagonist, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, and the dissociation constant (Kd) is 10−9 M (Cadepond (1997) Annu.Rev.Med. 48:129). Dazucortilant (CORT113176) is another such glucocorticoid receptor modulator compound and has been described in PCT Publication No. WO 2013 / 177559 and U.S. Patent No. 8,859,774. What is needed in the art is a novel method for preparing dazucortilant with a lower impurity content. Surprisingly, the present invention meets these and other needs.

Summary of the Invention

[0004] In some embodiments, the present invention provides a method for preparing a compound of formula I,

Chemical formula

Chemical formula

Chemical formula

[0005] In some embodiments, the present invention provides a method for preparing a compound of formula I below,

Chemical formula

Chemical formula

Chemical formula

[0006] In some embodiments, the present invention provides a method for preparing a compound of formula IIb below,

Chemical formula

Chemical formula

Chemical formula

[0007] In some embodiments, the present invention a compound of formula I in an amount of at least 99%,

Chemical formula

[0008] In some embodiments, the present invention provides crystalline (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonate,

Chemical formula

[0009] In some embodiments, the present invention provides a pharmaceutical composition comprising the low-impurity composition of the present invention and a pharmaceutically acceptable excipient.

[0010] 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 the low-impurity composition of the present invention or the pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0011] In some embodiments, the present invention provides a method for treating a disorder or condition by antagonizing the glucocorticoid receptor, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention with low impurities or a pharmaceutical composition of the present invention.

[0012] In some embodiments, the present invention provides a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of the present invention with low impurities or a pharmaceutical composition of the present invention, thereby treating fatty liver disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

[0014] I. General The present disclosure describes a new method for preparing a compound of formula I, (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 (dazucorilant), which has a lower impurity concentration than the aforementioned methods. The new method for preparing dazucorilant improves safety and cost-effectiveness and can be prepared on a larger scale compared to known methods. Dazucorilant can be prepared as in Example 1 of U.S. Patent No. 8,859,774. The present disclosure also describes a composition of dazucorilant having a lower impurity concentration.

[0015] II. Definitions "About" when referring to a value includes the recited value ± 10% of the recited value. For example, about 50% includes the range of 45% to 55%, while about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to ± 10% of the recited value for each of the upper and lower limits of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3.

[0016] "Forming a reaction mixture" refers to the step of contacting at least two separate species such that they can be mixed together and react. However, it will be understood that the resulting reaction product can be formed directly from the reaction between the added reagents or directly from an intermediate from one or more of the added reagents that are formed in the reaction mixture.

[0017] "Dissolve", "dissolving", or "dissolution" refers to a solid material that is substantially soluble in a particular solvent. For example, the solid material can be soluble in the solvent at greater than 90%, or at greater than 91, 92, 93, 94, 95, 96, 97, 98, or 99%.

[0018] "Distilling", "to distill", or "distillation" refers to the separation of components in a liquid mixture using a combination of temperature and pressure. The component of interest is converted from a liquid to a gas, and then the gas condenses back to a liquid, separating the component of interest from the other components of the mixture.

[0019] "Eluting", "to elute", or "elution" refers to the process of separating the component of interest from the other components in a mixture by passing the mixture over a stationary phase. The component of interest is eluted from the stationary phase using a mobile phase that may contain any suitable solvent or acid.

[0020] "Concentrating" or "to concentrate" refers to the process of removing a solvent or diluent from a mixture in order to increase the molar concentration of the components in the mixture. Concentration can be achieved by various methods such as distillation or rotary evaporation. Concentrating may involve removing some or all of the solvent or diluent.

[0021] "Precipitating", "precipitated", or "precipitation" refers to the formation of a solid from a solution such that a dissolved compound appears from the solution, for example by adding to an excess of a second solvent in which the compound is substantially insoluble, the first solvent in which the compound is dissolved.

[0022] "Substantially free of" means a composition in which an undesirable component is present in an amount less than 5% HPLC peak area, less than 1% HPLC peak area, less than 0.5% HPLC peak area, or even less than 0.1% HPLC peak area.

[0023] "Aqueous phase" refers to a mixture containing water.

[0024] "Organic phase" refers to a mixture containing a water-miscible or immiscible solvent that can dissolve either or both water-soluble and water-insoluble organic compounds. The organic phase of the present invention can be formed from one or more organic solvents. Exemplary organic solvents can include nonpolar aprotic solvents, polar aprotic solvents, and polar protic solvents. Representative solvents include, but are not limited to, pentane, hexanes, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, chloroform, and the like.

[0025] "Acid" refers to a compound that can donate a proton (H+) according to the Bronsted-Lowry definition, or a compound that is an electron pair acceptor according to the Lewis definition. Acids useful in the present invention include, but are not limited to, Bronsted-Lowry acids including alkanoic acids or carboxylic acids (such as formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids, and mineral acids described herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), halogen oxoacids (hypochlorous acid, perchloric acid, etc.), and sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfonic acids include, among others, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid.

[0026] "Grignard reagent" refers to a reagent containing a complex of metallic magnesium, a halide, and an alkyl ligand that can form a carbon-carbon bond. Representative Grignard reagents include, but are not limited to, iPrMgCl and iPrMgBr.

[0027] "Non-nucleophilic base" refers to a base that is moderately to strongly basic but has poor nucleophilicity. Representative non-nucleophilic bases include, for example, bases such as potassium carbonate, sodium carbonate, potassium t-butoxide, and sodium t-butoxide, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. Non-nucleophilic bases include non-nucleophilic amine bases.

[0028] "Solvent" refers to a substance, such as a liquid, that can dissolve a solute. Solvents can be polar or non-polar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater 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 protons available for removal, such as having a hydroxy group or a carboxy group, for example. Aprotic 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, diethyl ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents are useful in the present invention.

[0029] "Room temperature" is the range of air temperature that is normally considered suitable for human habitation, that is, between about 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0030] "Vacuum" or "reduced pressure" refers to a pressure that is less than atmospheric pressure. Atmospheric pressure is measured as approximately 1013 mbar, 760 mmHg, or approximately 14.7 psi. Therefore, a vacuum can be less than 1013 mbar, or less than 100, 10, 1, 0.1 mbar, or less than 0.01 mbar.

[0031] "Alkyl" refers to a straight-chain or branched saturated aliphatic group having the number of carbon atoms indicated. Alkyl can contain any number of carbons, such as, for example, C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. For example, C1-6 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.

[0032] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0033] "Haloalkyl" refers to alkyl as defined above, where some or all of the hydrogen atoms are replaced by halogen atoms. For an alkyl group, the haloalkyl group can have any suitable number of carbon atoms, such as, for example, C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. The term "perfluoro" can be used to indicate a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0034] "Pharmaceutically acceptable salts" refers to acidic or basic salts of the compounds used in the methods of the present invention. Exemplary examples of pharmaceutically acceptable salts include mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, methanesulfonic acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Further information regarding 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.

[0035] As used herein, "composition" is intended to encompass a product containing a specified amount of a specified ingredient, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0036] "Pharmaceutically acceptable excipients" refers to substances that assist in the administration of the active agent to the subject and its absorption by the subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0037] "To treat", "treating", and "treatment" refer to any indication that the treatment or amelioration of an injury, medical condition or state has been successful, and include, for example, alleviation, remission, and reduction of symptoms or the injury, medical condition or state becoming more tolerable to the patient, blunting of the rate of degeneration or decline, attenuation of the end point of degeneration, or improvement of the physical or mental well-being of the patient, including any objective or subjective parameter such as these. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0038] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device such as, for example, a mini osmotic pump, to a subject.

[0039] "Patient" or "subject" refers to a living body that has, or is at risk of having, a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, horses, and other non-mammalian animals. In some embodiments, the patient is human.

[0040] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease or condition or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend upon the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Pickar, Dosage Calculations (1999), and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0041] "Glucocorticoid receptor" ("GR") refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs such as, for example, dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0042] The cortisol receptor is the glucocorticoid receptor (GR), particularly the type II GR, which specifically binds cortisol and / or cortisol analogs such as, for example, dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0043] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (type I GR) that is activated by aldosterone in humans.

[0044] "Glucocorticoid Receptor Modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of a glucocorticoid receptor agonist. As used herein, with respect to GRM, the glucocorticoid receptor may be GR, or both. For example, a GRM that acts as an agonist such as dexamethasone increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human hepatocellular carcinoma cell line of the human liver; ECACC, UK). A GRM that acts as an antagonist such as mifepristone inhibits the agonist-induced increase in the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441 - 2452.

[0045] "Glucocorticoid Receptor Antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRA, the glucocorticoid receptor may be GR, or both. Thus, a GR antagonist can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441 - 2452. An inhibitor is a compound having an IC50 (half maximal inhibitory concentration) of less than 10 micromolar. See Example 1 of U.S. Patent No. 8,685,973, which is hereby incorporated by reference in its entirety.

[0046] "Adjust" and "adjusting" are used in their ordinary sense and refer to the action of changing or varying one or more properties. "Adjustment" refers to the process of changing or varying one or more properties. For example, when used in reference to the effect of a modulator on a target protein, adjusting means changing by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0047] "Modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of the target of the molecule.

[0048] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist to a receptor molecule or inhibiting the signal generated between the receptor and the agonist. A receptor antagonist inhibits or suppresses an agonist-mediated response such as gene expression.

[0049] "Antagonist" refers to a substance that can detectably decrease the expression or activity of a given gene or protein. An antagonist can inhibit the 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-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more than the expression or activity in the absence of the antagonist.

[0050] "Inhibit", "inhibiting", and "inhibitor" refer to a compound that interferes with a particular action or function, or a method of interfering with a particular action or function. "Disorder" or "condition" refers to the condition or health state of a patient or subject that can be treated with the glucocorticoid receptor modulators of the present invention. In some embodiments, examples of disorders or conditions include, but are not limited to, amyotrophic lateral sclerosis (ALS).

[0051] III. Method for Preparing Compound of Formula I from Formula IIa In some embodiments, the present invention provides a compound of formula I below,

Chem.

Chem.

Chem.

[0052] In some embodiments, HX is,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0053] In some embodiments, HX is

Chem.

Chem.

Chem.

Chem.

[0054] In some embodiments, HX is

Chem.

Chem.

[0055] In some embodiments, HX is

Chem.

[0056] In some embodiments, HX is MeS(O)2OH,

Chem.

Chem.

Chem.

[0057] In some embodiments, HX is MeS(O)2OH.

[0058] In some embodiments, the present invention provides a method for preparing a compound of formula I below,

Chemical formula

Chemical formula

Chemical formula

[0059] In some embodiments, the compound of formula I contains less than 1% of the following compound of formula X-5.

Chemical formula

[0060] The compound of formula I can be prepared from the compound of formula IIa.

Chemical formula

[0061] A. Preparation of Formula I from Formula IIa In some embodiments, the present invention provides a compound of formula I below,

Chemical formula

[0062] In some embodiments, the compound of formula I is prepared in at least 75% yield and at least 98% purity.

[0063] In some embodiments, R1 is C1-2 alkyl, C1-2 haloalkyl, phenyl, or 4-methylphenyl. In some embodiments, R1 is methyl, ethyl, -CF3, phenyl, or 4-methylphenyl. In some embodiments, R1 is methyl.

[0064] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of formula IIa can have the following structure. [Chemical formula]

[0065] In some embodiments, the first reaction mixture further comprises a non-nucleophilic amine base. Any suitable non-nucleophilic amine base can be used in the first reaction mixture. In some embodiments, the non-nucleophilic amine base comprises trimethylamine, triethylamine (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-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof. In some embodiments, the non-nucleophilic amine base comprises triethylamine.

[0066] The first reaction mixture can include any suitable solvent. For example, the solvent can be an organic solvent including, but not limited to, ethyl acetate, isopropyl acetate, and n-butyl acetate. In some embodiments, the first reaction mixture further comprises a first solvent. In some embodiments, the first solvent comprises ethyl acetate, isopropyl acetate, n-butyl acetate, or a mixture thereof. In some embodiments, the first reaction mixture further comprises ethyl acetate.

[0067] The sulfonyl chloride used in the first reaction mixture can be present in any suitable molar ratio relative to the compound of formula II or formula IIa. For example, the sulfonyl chloride can be present in a molar ratio of 0.5 to 2.0 relative to the compound of formula II or formula IIa, a molar ratio of 0.5 to 1.5, 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, or 0.9 to 1.1 relative to the compound of formula II or formula IIa. In some embodiments, the sulfonyl chloride is present in a molar ratio of 0.5 to 1.5 relative to the compound of formula IIa. The sulfonyl chloride can be present in a molar ratio of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 relative to the compound of formula II or formula IIa. In some embodiments, the sulfonyl chloride can be present in a molar ratio of about 1.0 relative to the compound of formula IIa.

[0068] 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%.

[0069] The compound of formula I can be prepared in any suitable purity. For example, the compound of formula I can be prepared in 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 in a purity of at least 96%. In some embodiments, the compound of formula I can be prepared in a purity of at least 97%. In some embodiments, the compound of formula I can be prepared in a purity of at least 98%. In some embodiments, the compound of formula I can be prepared in a purity of at least 99%.

[0070] In some embodiments, the method for preparing a 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 the sulfonyl chloride. In some embodiments, the amino scavenger comprises N-methylpiperazine, N1,N1-dimethylethane-1,2-diamine, N1,N1,N2-trimethylethane-1,2-diamine, or N1,N1-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.

[0071] The amino scavenger can be present in any suitable amount. For example, the amino scavenger can be present in a molar ratio of less than 1.0 relative to the compound of formula II or formula IIa, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.25 relative 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 relative to the compound of formula IIa.

[0072] In some embodiments, the method for preparing a compound of formula I further comprises the steps of (a2) adding a first acid and water to the first reaction mixture to partition 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.

[0073] The first acid can comprise any suitable acid. In some embodiments, the first acid comprises hydrochloric acid.

[0074] In some embodiments, the method for preparing a compound of formula I comprises the step of (a4) concentrating the first organic mixture, and the step of (a5) adding ethanol to the concentrated first organic mixture. The method further includes a step of adding water to the concentrated first organic mixture to precipitate the compound of formula I.

[0075] In some embodiments, the method for preparing the compound of formula I from the compound of formula IIa is (a) A compound of formula IIa having the following structure

Chemical formula

Chemical formula

[0076] The compound of formula I can be prepared by any acceptable amount of the following formula X-5.

Chemical formula

[0077] For example, the compound of formula I can be prepared to contain less than 5%, or less than 4, 3, 2, 1, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1% of the compound of formula X-5. In some embodiments, the compound of formula I can be prepared to contain less than 1% of the following compound of formula X-5.

Chem.

[0078] In some embodiments, the compound of formula I can be prepared to contain less than 0.75% of the compound of formula X-5. In some embodiments, the compound of formula I can be prepared to contain less than 0.5% of the compound of formula X-5. In some embodiments, the compound of formula I can be prepared to contain less than 0.1% of the compound of formula X-5.

[0079] B. Preparation of Formula IIa from Formula IIb The compound of formula IIa can be prepared from the compound of formula IIb. In some embodiments, the present invention provides a compound of formula IIa as follows,

Chem.

Chem.

Chem.

[0080] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of Formula IIa can have the following structure.

Chemical formula

[0081] The second reaction mixture can contain any suitable solvent. In some embodiments, the second reaction mixture contains a second solvent. Examples of the second solvent include, but are not limited to, pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, and chloroform. In some embodiments, examples of the second solvent include acetonitrile, cyclopentyl methyl ether (CPME), tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), methanol, ethanol, diethyl ether, methyl-t-butyl ether (MTBE), toluene, or combinations thereof. In some embodiments, the second reaction mixture contains acetonitrile.

[0082] C. Preparation of Formula III from Formula IIb The compound of Formula IIb can be prepared by various methods. In some embodiments, the compound of Formula IIb is (c) a Grignard reagent, a compound of Formula III below,

Chemical formula

Chemical formula

[0083] 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.

[0084] The Grignard reagent can be present in any suitable molar ratio relative to the compound of formula III. For example, the Grignard reagent can be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.3, 2.8 to 3.2, 2.9 to 3.2, 2.9 to 3.1 relative to the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.8 to 3.3 relative to the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.9 to 3.2 relative to the compound of formula III. The Grignard reagent can be present in a molar ratio of about 2.90, or about 2.95, 3.00, 3.05, 3.10, 3.15, or about 3.20 relative to the compound of formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 3.0 relative to the compound of formula III.

[0085] Pyridine may be present in any suitable ratio to the compound of formula III. For example, pyridine may be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.2, 2.9 to 3.1 with respect to the compound of formula III. In some embodiments, pyridine may be present in a molar ratio of 2.8 to 3.2 with respect to the compound of formula III. Pyridine may be present in a molar ratio of about 2.5, or about 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5 with respect to the compound of formula III. In some embodiments, pyridine may be present in a molar ratio of about 3.0 with respect to the compound of formula III.

[0086] The third reaction mixture may also contain a third solvent. The third solvent can be any suitable solvent including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further contains a third solvent. In some embodiments, the third solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further contains 2-methyltetrahydrofuran and toluene.

[0087] In some embodiments, the method for preparing the compound of formula IIb also includes (c1) adding a third acid and water to the third reaction mixture to form a work-up mixture, and (c2) distilling the work-up mixture to form an intermediate mixture containing the compound of formula IIb.

[0088] The third acid in step (c1) can be any suitable acid. In some embodiments, the third acid includes formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or mixtures thereof. In some embodiments, the third acid includes acetic acid.

[0089] In some embodiments, the second reaction mixture further comprises an intermediate mixture comprising a compound of formula IIb.

[0090] In some embodiments, the method for preparing a compound of formula IIa comprises (c) forming a third reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of the following formula III,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0091] In some embodiments, the present invention provides a method for preparing a compound of the following formula I,

Chemical formula

[0092] IV. Method for preparing formula IIb from formula III The compound of formula IIb can be prepared by any suitable method such as the method described for Intermediate 11 in US Patent No. 8,859,774. In some embodiments, the present invention provides a compound of formula IIb as follows,

Chemical formula

Chemical formula

Chemical formula

[0093] 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.

[0094] The Grignard reagent may be present in any suitable molar ratio to the compound of formula III. For example, the Grignard reagent may be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.3, 2.8 to 3.2, 2.9 to 3.2, 2.9 to 3.1 with respect to the compound of formula III. In some embodiments, the Grignard reagent may be present in a molar ratio of 2.8 to 3.3 with respect to the compound of formula III. In some embodiments, the Grignard reagent may be present in a molar ratio of 2.9 to 3.2 with respect to the compound of formula III. The Grignard reagent may 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 respect to the compound of formula III. In some embodiments, the Grignard reagent may be present in a molar ratio of about 3.0 with respect to the compound of formula III.

[0095] Pyridine may be present in any suitable ratio to the compound of formula III. For example, pyridine may be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.2, 2.9 to 3.1 with respect to the compound of formula III. In some embodiments, pyridine may be present in a molar ratio of 2.8 to 3.2 with respect to the compound of formula III. Pyridine may be present in a molar ratio of about 2.5, or about 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5 with respect to the compound of formula III. In some embodiments, pyridine may be present in a molar ratio of about 3.0 with respect to the compound of formula III.

[0096] The third reaction mixture may also contain a third solvent. The third solvent can be any suitable solvent including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further comprises a third solvent. In some embodiments, the third solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further comprises tetrahydrofuran and toluene.

[0097] In some embodiments, the method for preparing the compound of formula IIb also includes (c1) adding an acid and water to the third reaction mixture to form a work-up mixture, and (c2) distilling the work-up mixture to form an intermediate mixture containing the compound of formula IIb.

[0098] The acid in step (c1) can be any suitable acid. In some embodiments, the acid includes formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or mixtures thereof. In some embodiments, the acid includes acetic acid.

[0099] In some embodiments, the method for preparing the compound of formula IIb (c) forming a third reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of the following formula III,

Chemical formula

Chemical formula

Chemical formula

[0100] V. Composition with Low Impurities The present invention provides a composition of formula I with a low impurity content. The impurity content can be expressed in various different ways. For example, the impurity content can be expressed as %(HPLC peak area). In some embodiments, the impurity content can be expressed as %(HPLC peak area). In some embodiments, the present invention provides a composition comprising at least 99% by weight of the following compound of formula I, [Chemical formula] and from 0.01% to 1% by weight of one or more impurities.

[0101] The composition of formula I may contain one or more impurities present in a total amount of from 0.01% to 1%. In some embodiments, the impurities are compounds of formula X-A below in an amount of less than 0.5%, [Chemical formula] compounds of formula X-C below in an amount of less than 5%, [Chemical formula] compounds of formula X-5 below in an amount of less than 0.1%, [Chemical formula] and compounds of formula X-6 below in an amount of less than 0.1%, [Chemical formula] and containing at least one of the above.

[0102] The impurities present in the composition of the compound of formula I may contain the compound of formula X-A in an amount less than 1%. For example, the composition of the 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 0.1% of the compound of formula X-A. In some embodiments, the composition containing the compound of formula I may contain less than 0.5% of the compound of formula X-A. In some embodiments, the composition containing the compound of formula I may contain less than 0.3% of the compound of formula X-A. In some embodiments, the composition containing the compound of formula I may contain less than 0.1% of the compound of formula X-A.

[0103] The impurities present in the composition of the compound of formula I may contain the compound of formula X-C in an amount less than 1%. For example, the composition of the 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 0.1% of the compound of formula X-C. In some embodiments, the composition containing the compound of formula I may contain less than 0.5% of the compound of formula X-C. In some embodiments, the composition containing the compound of formula I may contain less than 0.3% of the compound of formula X-C. In some embodiments, the composition containing the compound of formula I may contain less than 0.2% of the compound of formula X-C. In some embodiments, the composition containing the compound of formula I may contain less than 0.1% of the compound of formula X-C. In some embodiments, the composition containing the compound of formula I may contain less than 0.05% of the compound of formula X-C.

[0104] The impurities present in the composition containing the compound of formula I may contain less than 1.0% of the compound of formula X-5, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1%. In some embodiments, the composition containing the compound of formula I may contain less than 0.25% of the compound of formula X-5. In some embodiments, the composition containing the compound of formula I may contain less than 0.2% of the compound of formula X-5. In some embodiments, the composition containing the compound of formula I may contain less than 0.1% of the compound of formula X-5.

[0105] The impurities present in the composition containing the compound of formula I may contain less than 1.0% of the compound of formula X-6, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, or 0.1%. In some embodiments, the composition containing the compound of formula I may contain less than 0.25% of the compound of formula X-6. In some embodiments, the composition containing the compound of formula I may contain less than 0.2% of the compound of formula X-6. In some embodiments, the composition containing the compound of formula I may contain less than 0.1% of the compound of formula X-6.

[0106] In some embodiments, the impurities include less than 0.1% by weight of the compound of formula X-A, less than 0.2% by weight of the compound of formula X-C, less than 0.1% by weight of the compound of formula X-5, and less than 0.1% by weight of the compound of formula X-6.

[0107] The impurities present in the composition containing the compound of formula I can contain ethyl 4-(trifluoromethyl)benzenesulfonate in an amount less than 100 ppm. For example, the composition containing the compound of formula I can contain ethyl 4-(trifluoromethyl)benzenesulfonate, which is an impurity, in an amount less than 100 ppm, or less than 90, 80, 75, 60, 50, 40, 30, or 25 ppm. In some embodiments, the composition containing the compound of formula I can contain ethyl 4-(trifluoromethyl)benzenesulfonate, which is an impurity, in an amount less than 25 ppm.

[0108] The impurities present in the composition containing the compound of formula I may contain 4-(trifluoromethyl)benzenesulfonyl chloride in an amount less than 100 ppm. For example, the composition containing the compound of formula I may contain 1-methyl-1H-pyrazole-4-sulfonyl chloride in an amount less than 100 ppm, or less than 90, 80, 75, 60, 50, 40, 30, 25, 20, 15, or 10 ppm. In some embodiments, the composition containing the compound of formula I may contain 4-(trifluoromethyl)benzenesulfonyl chloride in an amount less than 10 ppm.

[0109] 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.

[0110] In some embodiments, the composition containing the compound of formula I may contain, in an amount less than 0.1%, the following formula X-B,

Chemical formula

[0111] In some embodiments, the composition containing the compound of formula I may also contain the following impurities, a compound of the following formula X-D in an amount less than 2%,

Chemical formula

Chemical formula

[0112] In some embodiments, the composition containing the compound of formula I may contain a compound of the following formula X-H in an amount less than 0.15%,

Chemical formula

[0113] In some embodiments, a composition comprising a compound of Formula I also comprises the following impurities, less than 2% of the following compound of Formula X-D,

Chemical formula

Chemical formula

Chemical formula

[0114] VI. Crystalline Form of Formula IIa The present invention also provides crystalline salt forms of the 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 the following (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-nitrobenzoate

[0115] In some embodiments, the present invention provides crystalline forms of the following (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonate,

Chemical formula

[0116] In some embodiments, the XRPD further includes peaks at 2-theta of about 11.6, 21.3, 22.4 and 23.2° 2-theta ± 0.2°. In some embodiments, the XRPD further includes peaks at 2-theta of about 12.1, 14.4, 17.1, 20.4, 20.7, 20.9, 22.4, 26.2, 26.8, and 27.6° 2-theta ± 0.2° 2-theta. In some embodiments, the XRPD further includes peaks at 2-theta of about 7.8, 11.6, 12.1, 14.4, 14.7, 15.5, 17.1, 20.4, 20.7, 20.9, 21.3, 22.4, 23.2, 26.2, 26.8, and 27.6° 2-theta ± 0.2° 2-theta. In some embodiments, the crystalline form is characterized by an XRPD pattern substantially as described in Table 2. In some embodiments, the crystalline form is characterized by an XRPD pattern substantially as described in Figure 2.

[0117] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm associated with an onset at about 191°. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 3.

[0118] In some embodiments, the crystalline form is characterized by thermogravimetric analysis (TGA) substantially as shown in Figure 4.

[0119] In some embodiments, the present invention provides the 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 the 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 the 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.

[0120] VII. Compositions In some embodiments, the present invention provides a pharmaceutical composition comprising a composition of low impurities of the present invention and a pharmaceutically acceptable excipient.

[0121] The low-impurity composition of the present invention can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, solutions, troches, gels, syrups, slurries, suspensions, etc. suitable for ingestion by a patient. The low-impurity composition of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalants, e.g., intranasally. Further, the low-impurity composition of the present invention can be administered transdermally. The compound of formula I of the present invention can also be administered by an intraocular route, intravaginal route, and rectal route including suppositories, insufflations, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention also provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and / or excipients, and a compound of formula I. To prepare a pharmaceutical composition from the low-impurity composition of the present invention, the pharmaceutically acceptable carrier can be either solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details regarding the techniques of formulation and administration are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”).

[0122] In powders, the carrier is a finely divided solid which is in a mixture 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, and compressed into the desired shape and size.

[0123] The powder, capsule and tablet preferably contain 5% or 10% - 70% of the 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, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier which provides capsules in which the active ingredient, with or without other excipients, is surrounded by and thereby bound to the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0124] Suitable solid excipients include, but are not limited to, saccharide or protein fillers such as sugars including lactose, sucrose, mannitol, or sorbitol, starches from corn, wheat, rice, potato or other plants, celluloses such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose, and gums such as gum arabic and tragacanth, and proteins such as gelatin and collagen. If desired, disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate may be added.

[0125] The core of the dragee may also be provided with a suitable coating such as a concentrated sugar solution which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol 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 coating of the tablets or dragees for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally, for example, in push-fit capsules made of gelatin, as well as in soft, sealed capsules made of gelatin and using coatings such as glycerin or sorbitol. The push-fit capsules may contain a compound of formula I mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the case of soft capsules, the compound of formula I can be dissolved or suspended in a suitable liquid such as a fatty acid, liquid paraffin, or liquid polyethylene glycol, regardless of the presence or absence of a stabilizer.

[0126] To prepare a suppository, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of a convenient size and cooled, thereby solidifying it.

[0127] Preparations in liquid form include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. In the case of parenteral injection, the liquid preparation can be formulated as a solution in an aqueous polyethylene glycol solution.

[0128] Also included are preparations in solid form intended to be converted into a liquid form preparation for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0129] In an oily suspension, the compound of formula I can be formulated by suspending it in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. The oily suspension may contain a thickening agent such as beeswax, solid paraffin, or cetyl alcohol. A sweetening agent can be added to provide a palatable oral preparation such as glycerol, sorbitol, or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. See, for example, Minto, J. Pharmacol. Exp. Ther. 281:93 - 102, 1997 for an example of an injection oil vehicle. The pharmaceutical formulation of the present invention can also be in the form of a water-in-oil emulsion. The oily phase can be the vegetable oil or mineral oil described above, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums such as gum acacia and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion can also contain a sweetening agent and a flavoring agent, as seen in the formulations of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0130] The low-impurity composition of the present invention is delivered transdermally, by a topical route, and can be formulated as a topical stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, and aerosol.

[0131] The low-impurity composition of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered via intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), can be administered as biodegradable and injectable gel formulations (e.g., see Gao Pharm. Res. 12:857-863, 1995), or can be administered as microspheres for oral administration (e.g., see Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Either the transdermal or intradermal route results in constant delivery over several weeks or months.

[0132] In some embodiments, the formulation of the low-impurity composition of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by binding to liposomes that bind to cell surface membrane protein receptors that result in endocytosis, or by using ligands that bind directly to oligonucleotides. By using liposomes, particularly when the liposome surface has ligands specific for target cells or is otherwise preferentially directed to a particular organ, delivery of the GR modulator to target cells in vivo can be concentrated. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996, Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995, Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0133] The pharmaceutical preparation is preferably in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, i.e., a package containing individual amounts of the preparation such as tablets, capsules, and powders packaged in vials or ampoules. The unit dosage form can also be the capsule, tablet, cachet, or lozenge itself, or an appropriate number of any of these in a packaged form.

[0134] The amount of the active ingredient in the unit dose preparation can vary or be adjusted according to the particular use and the potency of the active ingredient, from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1000 mg, and most typically from 10 mg to 500 mg. For example, the dose can be 50 mg, or 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. The composition can also contain other compatible therapeutic agents, if desired.

[0135] The dosing regimen also takes into account pharmacokinetic parameters well known in the art, i.e., rates such as absorption, bioavailability, metabolism, clearance, etc. (see, e.g., Hidalgo - Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611 - 617, Groning (1996) Pharmazie 51:337 - 341, Fotherby (1996) Contraception 54:59 - 69, Johnson (1995) J. Pharm. Sci. 84:1144 - 1146, Rohatagi (1995) Pharmazie 50:610 - 613, Brophy (1983) Eur. J. Clin. Pharmacol. 24:103 - 108, and the latest Remington cited above). Depending on the state of the art, the clinician can determine the dosing regimen for an individual patient, GR and / or MR regulatory factors, and the disease or condition being treated.

[0136] Single or multiple administrations of the formulation can be administered according to the dosage and frequency required and tolerated by the patient. The formulation should provide an amount of the active agent sufficient to effectively treat the condition. Thus, in one embodiment, a pharmaceutical formulation for oral administration of a low impurity composition is in an amount of about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, the dosage is about 1 mg to about 20 mg per kilogram of body weight per patient per day. In contrast to oral administration, administration into the bloodstream, intracoelomic administration, or administration into the lumen of an organ, particularly when the agent is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) cavity, a lower dosage can be used. For topical administration, substantially higher dosages can be used. The actual methods for preparing formulations containing compounds of Formula I for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington above. See also Nieman, In “Receptor Mediated Antisteroid Action,” Agarwal, et al., eds., De Gruyter, New York (1987).

[0137] The low impurity compositions described herein can be used in combination with each other, in combination with other active agents known to be useful in modulating glucocorticoid receptors, or in combination with adjuvants that may not be effective alone but can contribute to the effectiveness of the active agent.

[0138] 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 the second active agent. Co - administration includes administering the two active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in either order. In some embodiments, co - administration can be achieved by co - formulation, i.e., by preparing a single pharmaceutical composition containing both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or excipients may be linked or conjugated to each other.

[0139] After a pharmaceutical composition comprising a compound of formula I of the invention is formulated in one or more acceptable carriers, it can be placed in a suitable container and labeled regarding the treatment of the designated condition. For administration of a compound of formula I, such labeling will include, for example, instructions regarding the amount, frequency, and method of administration.

[0140] In some embodiments, the low-impurity composition of the present invention is useful for parenteral administration, such as intravenous (IV) administration or administration into an organ's body cavity or lumen. The pharmaceutical formulation typically includes a solution of the composition of the present invention dissolved in one or more pharmaceutically acceptable carriers. Additionally, a sterile, non-volatile oil can be used as a solvent or suspending medium by conventional methods. For this purpose, any palatable non-volatile oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by conventional well-known sterilization techniques. The formulation may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusters and buffers, and isotonic agents, for example sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these formulations can vary widely and will be selected primarily based on factors such as the volume of fluid, viscosity, body weight, etc., depending on the particular administration method selected and the needs of the patient. For intravenous (IV) administration, the formulation can be a sterile injectable preparation, such as a sterile aqueous or oily suspension. This suspension can be formulated according to known techniques using their suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution.

[0141] VIII. Methods and Uses 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 one of the low-impurity compositions of the present invention or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0142] In some embodiments, the present invention provides a method of treating a disorder or condition by antagonizing the glucocorticoid receptor, the method comprising administering to a subject in need of such treatment an effective amount of any one of the compositions of low impurities of the present invention or a pharmaceutical composition of the present invention.

[0143] In some embodiments, the disorder or condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by cortisol excess associated with adrenal disease, addiction, psychosis, eating disorders, cachexia, post-traumatic stress disorder, postoperative fractures, GR-related metabolic disorders, psychotic major depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neonatal neuropathy.

[0144] In some embodiments, the method includes administering one or more second agents (e.g., therapeutic agents). In some embodiments, the method includes administering a therapeutically effective amount of one or more second agents (e.g., therapeutic agents). In some embodiments, the second agent is an agent known to be useful for modulating the glucocorticoid receptor. In some embodiments, the second agent is for treating amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by cortisol excess associated with adrenal disease, addiction, psychosis, eating disorders, cachexia, post-traumatic stress disorder, postoperative fractures, GR-related metabolic disorders, psychotic major depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological disorders in premature infants. In some embodiments, the second agent is for treating psychotic major depression, stress disorders, or antipsychotic-induced weight gain. In some embodiments, the second agent is for treating non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the second agent is for treating addiction disorders. In some embodiments, the second agent is for treating cancer. In some embodiments, the second agent is an anti-cancer agent. In some embodiments, the second agent is chemotherapy.

[0145] In some embodiments, any one of the low impurity compositions of the present invention, or the pharmaceutical composition of the present invention, can be used in a method for treating a disorder or condition by modulating the glucocorticoid receptor.

[0146] In some embodiments, any one of the low-impurity compositions of the present invention, or the pharmaceutical composition of the present invention, can be used in a method for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0147] In some embodiments, any one of the low-impurity compositions of the present invention, or the pharmaceutical composition of the present invention, can be used in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0148] In some embodiments, any one of the low-impurity compositions of the present invention, or the pharmaceutical composition of the present invention, can be used in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0149] In some embodiments, the present invention provides a method for treating amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof a therapeutically effective amount of the low-impurity composition of the present invention or the pharmaceutical composition of the present invention, thereby treating fatty liver disease. In some embodiments, any one of the low-impurity compositions of the present invention, or the pharmaceutical composition of the present invention, can be used in the manufacture of a medicament for treating amyotrophic lateral sclerosis (ALS).

Examples

[0150] IX. Examples In the following methods, the following abbreviations are used.

Table 1

[0151] Powder X-ray diffraction (XRPD). XRPD analysis was carried out using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. The isothermal samples were analyzed by the transmission method and held between low-density polyethylene films. The XRPD program used included the following parameters: (1) 2θ in the range 3 - 40°, (2) step size 0.013°, (3) count time 99 seconds, and (4) execution time of approximately 22 minutes. The XRPD patterns were sorted using HighScore Plus 2.2c software.

[0152] Differential scanning calorimetry (DSC). DSC analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. The accurately weighed samples were placed in an edge-folded aluminum pan. Each sample was heated to a maximum of 300 °C under nitrogen at a rate of 10 °C / min. Indium metal was used as the calibration standard. Temperatures were reported rounded to the second decimal place (0.01 degree) at the time of transition occurrence.

[0153] The reaction process of the present invention can be carried out for any suitable reaction time. For example, the reaction time can be in minutes, hours, or days. In some embodiments, the reaction time can be several hours, such as at least 8 hours. In some embodiments, the reaction time can be several hours, such as at least overnight. In some embodiments, the reaction time can be several days. In some embodiments, the reaction time can be at least two hours. In some embodiments, the reaction time can be at least eight hours. In some embodiments, the reaction time can be at least several days. In some embodiments, the reaction time can be about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 10 hours, or about 12 hours, or about 14 hours, or about 16 hours, or about 18 hours, or about 20 hours, or about 22 hours, or about 24 hours. In some embodiments, the reaction time can be about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or more than about 1 week.

[0154] The reaction process of the present invention can be carried out at any suitable reaction temperature. Representative temperatures include, but are not limited to, below room temperature, room temperature, or above room temperature. Other temperatures useful in the method of the present invention include from about -40°C to about 65°C, or from about room temperature to about 40°C, or from about 40°C to about 65°C, or from about 40°C to about 60°C. In some embodiments, the reaction mixture can be at a temperature of about room temperature, or about 15°C, or about 20°C, or about 25°C, or about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C.

[0155] Example 1. Preparation of (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 [Chemical formula]

[0156] Before use, two 400 L containers were boiled with ethyl acetate (A and B). Container A was used for the reaction, and an in-line filter was attached to Container B and used for the precipitation of dazucorilant (CORT113176). COR176-2 [15.692 kg, (11.948 kg, 31.91 corrected moles)] and ethyl acetate [213.8 kg, 235 L, 15 volumes] were charged into Container A. The contents were stirred for 5 minutes and then cooled to 0°C.

[0157] Triethylamine anhydrous [6.81 kg, 67.30 moles, 2.1 equivalents] was charged into Container A over 17 minutes while maintaining the batch temperature below 10°C. The contents of Container A were aged at 0°C for 51 minutes.

[0158] 4-(Trifluoromethyl)benzenesulfonyl chloride [7.960 kg, 32.54 moles, 1 equivalent] in ethyl acetate [27.4 kg, 31.4 L, 2 equivalents] was charged into Container A 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 the conversion of COR176-2 to dazucorilant.

[0159] N-Methylpiperazine [0.808 kg, 8.07 moles, 25 mol%] was charged into Container A. The batch was warmed to 20°C and aged for 3 hours.

[0160] Hydrochloric acid solution [0.5 M; 79 kg, 5 volumes] was charged into Container 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 volumes], the contents were aged for at least 10 minutes, and the aqueous layer was discarded.

[0161] Purified water [79 kg, 5 volumes] was charged into the container, the organic matter was washed for at least 10 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. This step was repeated twice.

[0162] The solution of dazucorilant was discharged into a drum and analyzed by HPLC for assay yield (for monitoring purposes only). 1-Methyl-4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine observed in the assay yield HPLC trace was not present (<0.04 A%).

[0163] Using ethyl acetate from the initial boil-out (boiling off and excluding), as part of the train, a foreign object test was conducted on vessel B using an oyster filter and API hose. This was to ensure that no solid contamination of the final API occurred.

[0164] The dazucorilant 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 volumes] under reduced pressure, and the batch temperature was maintained below 45°C. Ethanol [150 kg, 12 volumes] was charged to vessel B via a 1-micron in-line filter cartridge. The solution was then concentrated from approximately 220 L to 47 L [3 volumes] under reduced pressure, and the batch temperature was maintained below 45°C. The dazucorilant solution was cooled to 20°C and then analyzed by GC for ethyl acetate content.

[0165] The dazucorilant solution was transferred to a clean plastic-coated drum container [50 kg]. Ethanol [15.7 kg, 1.25 volumes] was charged to vessel B via a 1-micron in-line filter cartridge, the contents were stirred for 5 minutes, and combined with the dazucorilant solution. Ethanol [50 kg, 3 volumes] was charged to vessel B via a 1-micron in-line filter cartridge, the contents were stirred, and then discarded into a drum for waste. Purified water [236 kg, 15 volumes] was charged to vessel B via a 1-micron in-line filter cartridge. The dazucorilant solution was charged to vessel B over 38 minutes at a stirring speed of 170 rpm. The contents of vessel B were aged for 12 hours and then analyzed for solution loss (for information only).

[0166] The slurry was filtered and the filter cake was washed with purified water [47 kg, 3 volumes]. The solid was dried under a nitrogen stream for 5 hours and then dried in a vacuum oven at 60 °C for 64 hours. It contained 18.46 kg (99.3% with respect to COR176-2) of dazcolilant as a white solid.

[0167]

Table 2

[0168] The characteristic analysis data of the title compound were in agreement with those of Example 1 of US Patent No. 8,859,774.

[0169] Example 2. Preparation of (R)-1-(4-fluorophenyl)-4a-picolino-yl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium-methanesulfonate

Chem.

[0170] Method A Before use, a 400 L container was rinsed with toluene. COR176-1 [21.04 kg, 44.3 mol, 1.0 equivalent] as a stream in toluene [259.8 kg] was concentrated to 42 L [2 volumes] under reduced pressure while maintaining the batch temperature below 45 °C.

[0171] MeCN [166.1 kg] was added and the batch was concentrated from about 200 L to 42 L [2 volumes] 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.

[0172] The batch was cooled to 9.7 °C and MSA [17.14 kg, 178.3 mol, 4.0 equivalents] 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 a sample was taken to measure the reaction conversion by HPLC.

[0173] 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.

[0174] 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 minutes.

[0175] 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, then ethyl acetate [114 kg, 6 volumes] was added over 20 minutes. The batch was cooled to -19.7 °C over at least 2 hours, then samples were taken to measure the loss of liquidity by HPLC.

[0176] The batch was filtered, then quenched with THF [46.8 kg, 2.5 volumes and 37.1 kg, 2 volumes] and dried under nitrogen for 1 hour. The cake was dried under vacuum at 40 °C for 14 hours with a minimal nitrogen sweep and analyzed for weight percent. 15.81 kg of isolated COR176-2 was obtained (corresponding to an isolated yield of 73%, 76.14 wt% of COR176-2 (free base) in the salt).

[0177] Method B A 3 L round bottom flask was charged with 2151.22 g of COR176-1 in toluene [8.9% of COR176-1, 191.46 g of COR176-1]. The mixture was concentrated to 380 mL [2 volumes] under reduced pressure while maintaining the batch temperature below 45 °C.

[0178] MeCN [1493 g, 1900 mL] was added and the mixture was concentrated to 380 mL [2 volumes] under reduced pressure while maintaining the batch temperature below 45 °C. MeCN [239 g, 304 mL, 1.6 volumes] was added and samples were taken to measure the toluene content by GC. The mixture was transferred to a 2 L Radleys reactor while purging with nitrogen and cooled to 10 °C. Methanesulfonic acid [155 g, 105 mL, 4.0 eq] was added over 1 hour while maintaining the internal batch temperature below 15 °C. The batch was aged at 22 °C for 14 hours, after which a sample was taken and the reaction conversion by HPLC was measured.

[0179] The batch was cooled to 10 °C and Et3N [85 g, 117 mL, 2.1 eq] was added over at least 30 minutes while maintaining the internal temperature below 15 °C.

[0180] The batch was seeded with a slurry of COR176-2 (0.94 g, 0.5 mol%) and aged at 15 °C for 30 minutes.

[0181] 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, after which ethyl acetate [1028 g, 1140 mL, 6 volumes] was added over 20 minutes. The batch was cooled to -20 °C over at least 2 hours, after which a sample was taken and the liquid loss was measured by HPLC.

[0182] The batch was filtered, then washed twice with THF [425 g, 475 mL, 2.5 volumes and 338 g, 380 mL, 2 volumes] and dried under nitrogen flow for 1 hour. The cake was dried under vacuum at 40 °C for 12 hours with a minimal nitrogen sweep and analyzed for weight percent. 149.12 g of isolated COR176-2 was obtained (isolated yield 79%).

[0183]

Table 3-1

Table 3-2

[0184] Preparation of (R)-1-(4-fluorophenyl)-4a-picolinoyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium-ate [Chemical formula]

[0185] (R)-1-(4-Fluorophenyl)-4a-picolinoyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6-ium additional crystalline acid salts were prepared using dibenzoyl-L-tartaric acid, 4-nitrobenzoic acid, and (1S)-(+)-camphorsulfonic acid.

[0186] Example 4. Preparation of tert-butyl (R)-1-(4-fluorophenyl)-4a-picolinoyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylate [Chemical formula]

[0187] Before use, a 1000 L container was boiled with toluene. Compound 9 can be prepared according to Example 33 of US Patent No. 7,928,237. Compound 9 [19.48 kg, 45.6 mol, 1.0 equivalent] and toluene [84.6 kg, 97 L, 5 volumes] were charged into the container. The solid was then dissolved at 19 °C for 5 minutes, and the resulting solution was degassed three times under a positive pressure of nitrogen (the container was pressurized to 1000 bar g and vented to atmospheric pressure). The solution of Compound 9 was transferred to a clean plastic-coated drum container. The container was rinsed with toluene [67.6 kg, 78 L, 4 volumes] and then combined with the Compound 9 solution.

[0188] 2-Bromopyridine [21.84 kg, 138.2 mol, 3.0 eq] and toluene [168.8 kg, 195 L, 10 volumes] were charged into a vessel. The 2-bromopyridine solution was degassed three times under a positive pressure of nitrogen (the vessel was pressurized to 1000 barg and vented to atmospheric pressure).

[0189] Approximately 20% isopropylmagnesium chloride in THF [68.4 kg, 137.0 mol, 3.0 eq] was charged into 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.

[0190] A solution of Compound 9 was charged into 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 the conversion of Compound 9 (for monitoring purposes only). The reaction mixture was aged at 22 °C for a total of 2 hours.

[0191] The batch was cooled to 12 °C and charged with acetic acid [27.69 kg, 461.1 mol, 10.0 eq] over 1 hour while maintaining the batch temperature below 22 °C. The quenched mixture was aged for 17.75 hours and then samples were taken to monitor the reaction profile by HPLC (for monitoring purposes only).

[0192] 1 M hydrochloric acid solution [199 kg, 195 L, 10 volumes] was charged into the vessel, aged for 15 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. This process was repeated. Purified water [199 kg, 195 L, 10 volumes] was added to the vessel, aged for 15 minutes, allowed to settle in the biphasic mixture, and the aqueous layer was drained. This process was repeated once.

[0193] The organic stream was concentrated under reduced pressure from approximately 420 L to 293 L [15 volumes] while maintaining the batch temperature below 45 °C. The organic stream was cooled to 20 °C and transferred to a clean plastic-coated drum container. Samples were taken and analyzed for weight percent in solution (calculated 8.1 wt% - 21.34 kg in 263.4 kg of crude solution (assay yield 98.7%)).

[0194] The characteristic analysis data of the title compound was consistent with that of Intermediate 11 of U.S. Patent No. 8,859,774.

[0195] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. Further, each reference provided in this specification is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of any conflict between this application and the references provided herein, this application shall govern.

Claims

1. A composition, At least 99% of the following compound of formula I, 【Chemistry 1】 and a composition containing one or more impurities in an amount of 0.01 to 1%.

2. A pharmaceutical composition comprising the composition according to Claim 1 and one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 2, for use in treating a disorder or condition by modulating glucocorticoid receptors.

4. The pharmaceutical composition according to claim 2, for use in treating a disorder or condition by antagonizing glucocorticoid receptors.

5. The pharmaceutical composition according to claim 2, for use in treating amyotrophic lateral sclerosis (ALS).

6. The compound of formula I below, 【Chemistry 2】 or a method for preparing a pharmaceutically acceptable salt thereof, (a) Compounds of formula II below, 【Transformation 3】 and 4-(trifluoromethyl)benzenesulfonyl chloride 【Chemistry 4】 The process involves forming a first reaction mixture containing the above to prepare the compound of formula I in at least 60% yield and at least 98% purity, In the formula, the subscript n is 1 to 4. HX is 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 In the formula, R1 is C1-6 alkyl, C1-10 haloalkyl, phenyl, 4-methylphenyl, 4-NO2-phenyl, -OC(O)-phenyl, or 【Chemistry 10】 The method.

7. The method according to claim 6, wherein HX is MeS(O)2OH.

8. (a) Compounds of formula IIa below, 【Chemistry 11】 and 4-(trifluoromethyl)benzenesulfonyl chloride 【Chemistry 12】 The process involves forming the first reaction mixture containing the above to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%, The method according to claim 6, wherein R1 is a C1-6 alkyl, C1-10 haloalkyl, phenyl, or 4-methylphenyl, and the subscript n is 1 to 4.

9. The method according to claim 8, wherein the compound of formula I is prepared in a yield of at least 75% and a purity of at least 98%.

10. The method according to claim 8, wherein R1 is a C1-2 alkyl, a C1-2 haloalkyl, a phenyl, or a 4-methylphenyl.

11. The method according to claim 8, wherein R1 is methyl, ethyl, -CF3, phenyl, or 4-methylphenyl.

12. The method according to claim 8, wherein n is 1.

13. The method according to claim 6, wherein the first reaction mixture further comprises a non-nucleophilic amine base.

14. The method according to claim 13, wherein the non-nucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof.

15. The method according to claim 6, wherein the first reaction mixture further comprises the first solvent.

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

17. The method according to claim 8, wherein the sulfonyl chloride is present in a molar ratio of about 1.0 with respect to the compound of formula IIa.

18. The method according to claim 6, (a1) A method comprising the step of adding an amino scavenger to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride.

19. The method according to claim 18, wherein the amino scavenger comprises N-methylpiperazine, N1,N1-dimethylethane-1,2-diamine, N1,N1,N2-trimethylethane-1,2-diamine, or N1,N1-bis(2-aminoethyl)ethane-1,2-diamine.

20. The method according to claim 18, wherein the amino scavenger is present in a molar ratio of about 0.25 with respect to the compound of formula IIa.

21. (a2) A step of adding the first acid and water to the first reaction mixture to separate the first reaction mixture into the first aqueous mixture and the first organic mixture, (a3) The method according to claim 18, further comprising the step of separating the first aqueous mixture from the first organic mixture.

22. The method according to claim 21, wherein the first acid includes hydrochloric acid.

23. (a4) A step of concentrating the first organic mixture, (a5) A step of adding ethanol to the concentrated first organic mixture, (a6) The method according to claim 21, further comprising the step of adding water to the concentrated first organic mixture to precipitate the compound of formula I.

24. (a) A compound of formula IIa having the following structure, 【Chemistry 13】 Triethylamine, ethyl acetate, and 4-(trifluoromethyl)benzenesulfonyl chloride, 【Chemistry 14】 A step of forming the first reaction mixture comprising the sulfonyl chloride present in a molar ratio of about 1.0 relative to the compound of formula IIa, (a1) Adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride, (a2) A step of 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) A step of separating the first aqueous mixture from the first organic mixture, (a4) A step of concentrating the first organic mixture, (a5) A step of adding ethanol to the concentrated first organic mixture, (a6) The method according to claim 6, comprising the step of adding water to the concentrated first organic mixture to precipitate the compound of formula I in a yield of at least 75% and a purity of at least 98%.

25. The method according to any one of claims 6 to 24, wherein the compound of formula I contains less than 1% of the following compounds of formula X-5. 【Chemistry 15】

26. The compound of formula IIa below, 【Chemistry 16】 A method for preparing, (b) Compound of formula IIb, 【Chemistry 17】 and sulfonic acid in the following formula, [Chemistry 18] The process involves forming a second reaction mixture containing the compound of formula IIa, A method wherein R1 is a C1-6 alkyl, C1-10 haloalkyl, phenyl, or 4-methylphenyl, and the subscript n is 1 to 4.

27. The compound of formula I below, 【Chemistry 19】 or a method for preparing a pharmaceutically acceptable salt thereof, (c) Tetrahydrofuran, toluene, iPrMgCl, and the compound of formula III below, 【Chemistry 20】 and 2-bromopyridine, 【Chemistry 21】 The process involves forming a third reaction mixture containing, wherein the pyridine is present in a molar ratio of about 3.0 relative to the compound of formula III, and the Grignard reagent is present in a molar ratio of about 3.0 relative to the compound of formula III. (c1) Adding acetic acid and water to the third reaction mixture to form a work-up treatment mixture, (c2) The work-up mixture is distilled to form an intermediate mixture containing the compound of formula IIb below, 【Chemistry 22】 (b) Form a second reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid to form a compound of formula IIa having the following structure: 【Chemistry 23】 (a) The compound of formula IIa, triethylamine, ethyl acetate, and the following 4-(trifluoromethyl)benzenesulfonyl chlorides, 【Chemistry 24】 The first reaction mixture containing the following is formed: The sulfonyl chloride is present in a molar ratio of approximately 1.0 relative to the compound of formula IIa, forming a first reaction mixture. (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 divide 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, (a6) A method comprising adding water to the concentrated first organic mixture to precipitate the compound of formula I in a yield of at least 75% and a purity of at least 98%.

28. The compound of formula IIb below, 【Chemistry 25】 A method for preparing, (c) Grignard reagent, compound of formula III below, 【Chemistry 26】 and 2-bromopyridine, 【Chemistry 27】 A method comprising the step of forming a third reaction mixture containing, wherein the pyridine is present in a molar ratio of 2.8 to 3.2 relative to the compound of formula III, and the Grignard reagent is present in a molar ratio of 2.8 to 3.3 relative to the compound of formula III, to prepare the compound of formula IIb.

29. (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone in crystalline form, (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanonemethanesulfonic acid, (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone camphor sulfonic acid, (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanonedibenzoyl-L-tartaric acid, or The crystalline form is (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone 4-nitrobenzoic acid.

30. (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanomethanesulfonic acid in crystalline form, 【Chemistry 28】 The crystalline morphology is characterized by a powder X-ray diffraction (XRPD) pattern with peaks at approximately 7.8, 14.7, and 15.5°, and 2-θ ± 0.2°.

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