Methods and compositions for treating HSD-1-mediated disorders

Abstract

Processes for preparing triazole derivatives and compositions for use as HSD-1 inhibitors are provided.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 478,792, filed January 6, 2023, the contents of which are incorporated by reference as if set forth in their entirety herein. [Background technology]

[0002] Glucocorticoids (GCs) are corticosteroids that bind to glucocorticoid receptors (GRs) present in many cell types in the human body. GCs are involved in cardiovascular, metabolic, immune, bone, muscle, skin, ocular, mental, cognitive, circadian, and homeostatic functions. Additionally, GCs can also bind to mineralocorticoid receptors (MRs) and non-genomic receptors.

[0003] Important natural GCs include cortisol (known medically as hydrocortisone) and corticosterone. Synthetic GCs include prednisolone, methylprednisolone, dexamethasone, and many others, as well as their derivatives. Furthermore, inactive congeners (e.g., cortisone, prednisone) that do not activate GR are commonly referred to as GCs. Both cortisol and synthetic GCs are used as drugs to treat autoimmune diseases and other conditions. However, excess levels of either natural or synthetic GCs in humans can cause a myriad of symptoms and illnesses, including hyperglycemia, insulin resistance, obesity, hyperlipidemia, hypertension, and Cushing's syndrome. Such excess levels are most commonly caused by tumors secreting cortisol or hormones that increase cortisol secretion (e.g., ACTH or CRH), or by excessive administration of hydrocortisone or synthetic GCs during medical treatment.

[0004] 11β-hydroxysteroid dehydrogenase (HSD) is an enzyme that regulates intracellular levels of glucocorticoids. The HSD enzyme consists of two isoforms: nicotinamide-adenine dinucleotide phosphate-dependent type 1 (HSD-1), which converts inactive cortisone to active cortisol, and nicotinamide-adenine dinucleotide phosphate-dependent type 2 (HSD-2), which converts cortisol to cortisone. HSD-1 is thought to be the major source of intracellular cortisol and the primary source of intracellularly synthesized GCs in many cell types. Excess intracellular GCs activate GRs and MRs, along with non-genomic receptors, resulting in tissue-specific diseases observed in subjects with GC excess. Therefore, inhibition of HSD-1 may ameliorate these symptoms.

[0005] Novel potent HSD-1 inhibitors, including 4-(5-(2-(4-chloro-2,6-difluorophenoxy)propan-2-yl)-4-methyl-4h-1,2,4-triazol-3-yl)-3-fluorobenzamide and related compounds, are described in U.S. Pat. No. 8,377,923 (Patent Document 1), the entire contents of which are incorporated herein by reference, as promising potential inhibitors of HSD-1.

[0006] A need exists for new and improved methods for producing 4-(5-(2-(4-chloro-2,6-difluorophenoxy)propan-2-yl)-4-methyl-4h-1,2,4-triazol-3-yl)-3-fluorobenzamide and related compounds that are amenable to large-scale high-purity synthesis for use as HSD-1 inhibitors for the treatment of HSD-1-mediated diseases.

[0007] Citation of any reference throughout this application should not be construed as an admission that such reference is prior art to the present application. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 8,377,923 Summary of the Invention

[0009] overview Compounds of structural formula II: TIFF2026501779000001.tif28164 is provided.

[0010] Compounds of formula XIII: TIFF2026501779000002.tif22165 is also provided.

[0011] Compound of formula XIV: TIFF2026501779000003.tif27165 is also provided.

[0012] A compound of structural formula I: TIFF2026501779000004.tif24165 or a salt thereof, wherein the compound has an undetectable amount of structural formula II: Compositions containing TIFF2026501779000005.tif29165 are also provided.

[0013] A compound of structural formula I: TIFF2026501779000006.tif25165 or a salt thereof, wherein the composition comprises a compound of structural formula XIII in an amount of about 0.20% or less, and wherein the compound of structural formula XIII is present in an amount of about 0.20% or less. Compositions containing TIFF2026501779000007.tif22165 are also provided.

[0014] A compound of structural formula I: TIFF2026501779000008.tif25165 or a salt thereof, wherein the composition comprises a compound of structural formula XIV in an amount of about 0.20% or less, and wherein the compound of structural formula XIV is a compound of structural formula XIV: Compositions containing TIFF2026501779000009.tif27165 are also provided.

[0015] Pharmaceutical compositions comprising the compositions described herein and a pharmaceutically acceptable carrier are also provided.

[0016] Also provided is a method for treating an HSD-1 mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition or pharmaceutical composition described herein.

[0017] Also provided is a method for treating GC excess or a condition in a subject in need thereof, comprising administering a therapeutically effective amount of the composition or pharmaceutical composition described herein to the subject. GC excess conditions include Cushing's syndrome and autonomic cortisol secretion. GC excess can also be caused by the use of one or more GC drugs.

[0018] These and other aspects of the disclosure disclosed herein will be explained in more detail as the patent disclosure proceeds. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description Abbreviations and Definitions To facilitate understanding of this disclosure, some terms and abbreviations used herein are defined below.

[0020] When introducing elements of the disclosure or preferred embodiment(s) thereof, the articles "a," "an," "the," and "the" are intended to mean that there are one or more elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0021] When a range of values ​​is disclosed and the notation "n1... to n2" or "between n1... and n2" is used, where n1 and n2 are numbers, this notation is intended to include those numbers themselves and the range therebetween unless otherwise specified. The range may be integer or continuous between the endpoints and may be inclusive. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. Compare, as an example, the range "1 to 3 μM (micromolar)." This range is intended to include 1 μM, 3 μM, and all numbers therebetween to any number of significant digits (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0022] The term "about," as used herein in reference to measurable values ​​such as compound amount, dose, time, and temperature, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.

[0023] The term "detectable" refers to a measurable amount as determined using an HPLC method with a detection limit of 0.05 area %.

[0024] The term "chlorinating reagent," as used herein, refers to a compound or salt that adds chlorine atom(s) to an organic compound in a chemical reaction.

[0025] The term "hydrating agent," as used herein, refers to a compound, salt, catalyst, or combination thereof that results in the net addition of one or more molecules of water to an organic compound in a chemical reaction.

[0026] The term "intermediate," as used herein, refers to the primary organic product of a chemical reaction, or a salt thereof, that is not isolated or purified (i.e., the "crude product") prior to proceeding to the next step in the process.

[0027] The term "non-nucleophilic base" as used herein refers to a sterically hindered organic base that is a weak nucleophile. Examples of non-nucleophilic bases include N,N-diisopropylethylamine (DIPEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-dimethylpyridine (2,6-lutidine), 2,6-di-tert-butylpyridine, tert-butyllithium, tert-butylphosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidide (LiTMP), sodium hydride, potassium hydride, sodium tert-butoxide, and potassium tert-butoxide.

[0028] The term "nucleophilic catalyst," as used herein, refers to a Lewis base that catalyzes the reaction of compounds through the donation of an electron pair.

[0029] The term "polar solvent," as used herein, refers to a solvent with a large dipole moment.

[0030] The term "polar aprotic solvent," as used herein, refers to a polar solvent that lacks an acidic hydrogen. Therefore, they are not hydrogen bond donors. Examples of polar aprotic solvents include acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, and tetrahydrofuran (THF).

[0031] The term "disease," as used herein, is generally intended to be synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all terms reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by distinct signs and symptoms, and reduces the duration or quality of the human or animal's life.

[0032] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single dosage unit having a fixed ratio of active ingredients or in multiple separate dosage units for each active ingredient. In some embodiments, the dosage unit is a tablet. Furthermore, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0033] The phrase "therapeutically effective" is intended to modify the amount of active ingredient used to treat a disease or disorder or to achieve a clinical endpoint.

[0034] The term "therapeutically acceptable" refers to a compound (or salt) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, and that is effective for its intended use, commensurate with a reasonable benefit / risk ratio.

[0035] As used herein, "treating" and "treatment" refer to the administration of a therapy to an individual who already exhibits at least one symptom of a disease or condition, or to an individual who previously exhibited at least one symptom of a disease or condition. For example, "treating" can include alleviating, attenuating, or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating the underlying metabolic cause of the symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, reducing the pathology caused by a disease or condition, or arresting the symptoms of a disease or condition. For example, the term "treating" in reference to a disorder refers to a reduction in the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, nor does it necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0036] The term "patient" is generally synonymous with the term "subject" and includes all animals, including humans. Examples of patients include humans and primates, such as cynomolgus monkeys. Preferably, the patient is human.

[0037] The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts may be useful in the preparation and purification of the subject compounds. Basic addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich, Wiley-VCHA, Zurich, Switzerland, 2002).

[0038] The term "therapeutically acceptable salts," as used herein, refers to water- or oil-soluble or dispersible, therapeutically acceptable salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds, or can be prepared separately by reacting the appropriate compound in its free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, and mesitylenesulfone. Acid salts include, but are not limited to, sodium nitrate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfate; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids, such as oxalic acid, maleic acid, succinic acid, and citric acid.Salts can also be formed by coordination of the compounds with alkali metal or alkaline earth ions. Thus, the present invention contemplates sodium, potassium, magnesium, calcium, and the like salts of the compounds disclosed herein.

[0039] Base addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0040] In the examples below and throughout this disclosure, the following abbreviations may be used: Boc = tert-butyloxycarbonyl, DMSO = dimethyl sulfoxide, DCM = dichloromethane, DMAP = 4-dimethylaminopyridine, DMF = dimethylformamide, EtOAc = ethyl acetate, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EtOH = ethanol, TsOH = p-toluenesulfonic acid, 1 H-NMR = proton nuclear magnetic resonance, HPLC = high performance liquid chromatography, UPLC = ultra performance liquid chromatography, TLC = thin layer chromatography. Other abbreviations may be used and will be familiar in context to those skilled in the art.

[0041] Compounds and Compositions Compounds of structural formula II: TIFF2026501779000010.tif23165 is provided.

[0042] A compound of structural formula I: TIFF2026501779000011.tif26165 or a salt thereof, wherein the compound has an undetectable amount of structural formula II: Compositions containing TIFF2026501779000012.tif23165 are also provided.

[0043] Compounds of formula XIII: TIFF2026501779000013.tif22165 is also provided.

[0044] A compound of structural formula I: TIFF2026501779000014.tif25165 or a salt thereof, wherein the composition comprises a compound of structural formula XIII in an amount of about 0.2% or less, and wherein the compound of structural formula XIII is present in an amount of about 0.2% or less. Compositions containing TIFF2026501779000015.tif22165 are also provided.

[0045] Compound of formula XIV: TIFF2026501779000016.tif27165 is also provided.

[0046] A compound of structural formula I: TIFF2026501779000017.tif26165 or a salt thereof, wherein the composition comprises a compound of structural formula XIV in an amount of about 0.2% or less, and wherein the compound of structural formula XIV is present in an amount of about 0.2% or less. Compositions containing TIFF2026501779000018.tif27165 are also provided.

[0047] Prior Art Process U.S. Pat. No. 8,377,923 ('923) reports that a compound of Formula I designated as Example 186 of '923 was prepared using the process of Example 15 of '923 with appropriate starting materials as shown in the following scheme: The coupling step was carried out using imidoyl chloride 102 and propanohydrazide 103 in a 1:1 ratio at temperatures between 70 and 100°C, utilizing DMF as the solvent without any additional base. The coupled product was subsequently cyclized to the triazole with HCl in ethyl acetate, followed by hydration with sodium hydroxide and hydrogen peroxide. '923 does not provide purity or yield information for either Example 15 or Example 186.

[0048] Scale-up process Subsequently, a process was developed for the large-scale synthesis of the compound of Formula I. The coupling step was carried out using 1.2 equivalents of imidoyl chloride in DMAc / HO with 1.5 equivalents of lutidine as the base at temperatures between 0 and 10° C. Although the yield improved with increasing amounts of imidoyl chloride, this process did not produce detectable amounts of the compound of structural formula II: TIFF2026501779000020.tif30165 was produced and it was found that this compound survived through subsequent work-up and purification steps and remained in the final product.

[0049] Improved scale-up process A large-scale synthetic process for preparing compositions of Formula I with undetectable amounts of the compound of Formula II has been discovered. This novel process is based on the discovery that the formation of the compound of Formula II can be reduced, if not completely suppressed, by using dichloromethane as the solvent for the coupling step. The solvent switch allows for greater reactivity between the starting materials, reduces reaction time, and allows the use of limited amounts of imidoyl chloride while maintaining yield. Furthermore, the favorable partition coefficient of dichloromethane allows additional impurities, including DMF-related impurities formed during the synthesis of imidoyl chloride, to pass through to the discarded aqueous layer during workup. This process affords the compound of Formula IV: TIFF2026501779000021.tif21165, or a salt thereof, is reacted with a chlorinating agent and a catalyst to produce an intermediate of structural formula V: TIFF2026501779000022.tif21165 and this intermediate is reacted with dichloromethane to form a compound of formula III: and a non-nucleophilic base to give a second intermediate of formula VI: TIFF2026501779000024.tif24165 and reacting this second intermediate with a strong acid to give a triazole intermediate of formula XII: and subjecting this triazole intermediate to hydration conditions to provide the compound of formula I.

[0050] In some embodiments, the chlorinating reagents are independently selected from thionyl chloride, oxalyl chloride, and phosphoryl chloride.

[0051] In some embodiments, the chlorinating reagent is thionyl chloride.

[0052] In some embodiments, the catalyst is dimethylformamide.

[0053] In some embodiments, the chlorinating reagent is used in about a 1.5:1 to 4:1 molar excess relative to the compound of formula IV or V or intermediate.

[0054] In some embodiments, the non-nucleophilic base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), pyridine, 2,6-dimethylpyridine (2,6-lutidine), and 2,6-di-tert-butylpyridine.

[0055] In some embodiments, the non-nucleophilic base is 2,6-lutidine.

[0056] In some embodiments, the non-nucleophilic base is used in about a 1.1:1 to 3:1 molar excess relative to the intermediate of formula III.

[0057] In some embodiments, the strong acid is selected from hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, perchloric acid, chloric acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid.

[0058] In some embodiments, the strong acid is p-toluenesulfonic acid.

[0059] In some embodiments, the hydrating conditions are potassium carbonate and hydrogen peroxide.

[0060] In some embodiments, the compound of Formula III is a compound of structural formula VIII: TIFF2026501779000026.tif22165 or a salt thereof is reacted with ethyl 2-bromo-2-methylpropanoate and a base to produce an intermediate of formula IX: TIFF2026501779000027.tif21165 and hydrolyzing this intermediate to form an intermediate of structural formula X: TIFF2026501779000028.tif21165 and reacting this intermediate with tert-butyl carbazate, a carbodiimide, and a nucleophilic catalyst to form a second intermediate of structure XI: TIFF2026501779000029.tif22165 and subsequently reacting this second intermediate with a strong acid to form the compound of formula III.

[0061] In some embodiments, the carbodiimide is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0062] In some embodiments, the carbodiimide is EDC.

[0063] In some embodiments, the nucleophilic catalyst is selected from 4-dimethylaminopyridine (DMAP) and hydroxybenzotriazole (HOBt).

[0064] In some embodiments, the nucleophilic catalyst is 4-dimethylaminopyridine (DMAP).

[0065] In some embodiments, the strong acid is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid.

[0066] In some embodiments, the strong acid is hydrochloric acid.

[0067] In some embodiments, ethyl 2-bromo-2-methylpropanoate is used in about a 1.5:1 to 3:1 molar excess relative to the compound of Formula VIII.

[0068] In some embodiments, the base is selected from sodium carbonate and potassium carbonate.

[0069] In some embodiments, the base is potassium carbonate.

[0070] In some embodiments, the base is used in about a 1.5:1 to 3:1 molar excess relative to the compound of Formula VIII.

[0071] Pharmaceutical Composition Although the compounds and salts described herein may be administered as the raw chemical, they can also be presented as pharmaceutical formulations. Thus, provided herein are pharmaceutical formulations comprising one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Appropriate formulations depend on the chosen route of administration. Any well-known techniques, carriers, and excipients may be used, as appropriate, and as understood in the art. The pharmaceutical compositions disclosed herein may be prepared by any method known in the art, for example, by conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0072] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, intranasal, pulmonary (including inhalation and aerosol), transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound described herein or a pharmaceutically acceptable salt thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0073] It will be understood that in addition to the ingredients particularly mentioned above, the above formulations may include other agents conventionally used in the art having regard to the type of formulation in question (e.g., those suitable for oral administration may include flavoring agents).

[0074] The compounds and salts described herein may be administered orally or by injection at a dose of 0.001 to 500 mg / kg per day. The dose range for adult humans is generally 0.1 mg to 2 g per day. Tablets or other presentation forms provided in discrete units may conveniently contain units containing an effective amount of one or more compounds in such a dose, or multiples thereof, e.g., 0.05 mg to 500 mg, usually about 0.2 mg to 200 mg.

[0075] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.

[0076] The compounds and salts described herein can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level for any particular patient depends on various factors, including the activity of the specific compound used, the patient's age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated. In addition, the administration route may vary depending on the condition and its severity.

[0077] Indications and treatment methods Also provided is a method for treating an HSD-1 mediated disorder in a human or animal subject in need thereof, comprising administering to the subject an amount of a compound disclosed herein, or a salt thereof, or a composition thereof.

[0078] Also provided is a method for treating glucocorticoid excess or a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition disclosed herein or a salt thereof or composition thereof.

[0079] In some embodiments, the glucocorticoid excess condition is Cushing's syndrome.

[0080] In some embodiments, Cushing's syndrome can be caused by any of the rare disorders such as Cushing's disease, adrenal Cushing's syndrome, ectopic ACTH secretion, ectopic CRH secretion, or Carney complex.

[0081] In some embodiments, the glucocorticoid excess condition is autonomous cortisol secretion (also known as mild autonomous cortisol secretion, mild [autonomous] hypercortisolism, subclinical Cushing's syndrome, or hidden hypercortisolism).

[0082] In some embodiments, the state of glucocorticoid excess is caused by the use of one or more glucocorticoid drugs.

[0083] Also provided are methods for reducing the severity of one or more side effects of treatment with one or more glucocorticoid agents in a subject.

[0084] In some embodiments, the side effect is selected from osteoporosis, avascular osteonecrosis, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, fatty liver, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, skin porousness, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection.

[0085] In some embodiments, the HSD-1 mediated disorder is selected from diabetes, non-alcoholic fatty liver disease, idiopathic intracranial hypertension, diabetic wound healing, hyperglycemia, insulin resistance, obesity, hyperlipidemia, and hypertension.

[0086] In some embodiments, the HSD-1 mediated disorder is selected from diabetes, hyperlipidemia, non-alcoholic fatty liver disease, obesity, idiopathic intracranial hypertension, and diabetic wound healing.

[0087] In addition to being useful for human treatment, certain compounds, salts, and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals and reptiles. [Example]

[0088] Synthesis method The invention described below is further illustrated by the following examples: All IUPAC names were generated using CambridgeSoft's ChemDraw 21.0.

[0089] In the examples below and throughout this disclosure, the following abbreviations may be used: Boc = tert-butyloxycarbonyl, DMSO = dimethyl sulfoxide, DCM = dichloromethane, DMAP = 4-dimethylaminopyridine, DMF = dimethylformamide, EtOAc = ethyl acetate, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EtOH = ethanol, TsOH = p-toluenesulfonic acid, 1 H-NMR = proton nuclear magnetic resonance, HPLC = high performance liquid chromatography, UPLC = ultra performance liquid chromatography, TLC = thin layer chromatography. Other abbreviations may be used and will be familiar in context to those skilled in the art.

[0090] Example 1 TIFF2026501779000030.tif104165

[0091] Step 1 A mixture of 4-chloro-2,6-difluorophenol (Formula VIII, 1.0 equiv.) and ethyl α-bromoisobutyrate (2.0 equiv.) in DMF (5 vol.) was cooled to between 0 and 10 °C. KCO (1.5 equiv.) in DMF (5 vol.) was added, and the mixture was warmed to 50 ± 5 °C and stirred for 20 h. The reaction mixture was poured into a separate vessel containing water (10 vol.) and ethyl acetate (20 vol.). The organic layer was separated, neutralized with 1 M HCl (10 vol.), and washed with 30% brine (10 vol.). The organic layer was then concentrated to approximately 2 vol., solvent switched to ethanol, and concentrated to approximately 2 vol. The crude ethanol solution containing the compound of Formula IX was used in the next step without further purification.

[0092] Step 2 To the crude ethanol solution (2 volumes) from step 1 was charged an additional 10 volumes of EtOH and cooled to between 0 and 10 °C. NaOH (2.0 equiv.) in water (7 volumes) was added, and the mixture was stirred at 25 ± 5 °C for 1 hour. The reaction mixture was neutralized with 6 M HCl (2 volumes) and then concentrated to approximately 7 volumes. Ethyl acetate (17 volumes) was added and stirred for 30 minutes. The organic layer was then separated, washed with 30% brine (10 volumes), concentrated, solvent switched to ethyl acetate, followed by acetonitrile, and then concentrated again to approximately 3.5 volumes. The crude solution containing the compound of formula X was used in the next step without further purification.

[0093] Step 3 To the crude acetonitrile solution (3.5 volumes) from Step 2 was added t-butyl carbazate (1.05 equiv.), DMAP (0.05 equiv.), and an additional 7 volumes of acetonitrile. The mixture was cooled to between 0 and 10 °C, and EDC (1.2 equiv.) was added and stirred at 25 ± 5 °C for 1 hour. The reaction mixture was concentrated to approximately 3 volumes. Ethyl acetate (23 volumes) and 0.5 M HCl (7.5 volumes) were added and stirred for 15 minutes. The organic layer was separated, washed with 30% brine (10 volumes), concentrated, solvent switched to ethyl acetate, and then concentrated again to approximately 3 volumes. The crude solution containing the compound of Formula XI was used in the next step without further purification.

[0094] Step 4 The crude ethyl acetate solution from step 3 (3 volumes) was dissolved in an additional 2 volumes of ethyl acetate and then poured into a 4N solution of HCl in ethyl acetate (4.5 equivalents) at 0-10°C and stirred at 25±5°C for 20 hours. The reaction mixture was then concentrated to approximately 2 volumes. Ethyl acetate (2 volumes) was added, and the reaction mixture was stirred for 30 minutes. The resulting crystals were filtered, washed with ethyl acetate (4 volumes), and dried in a vacuum oven at 40°C to afford compound of Formula III (90.9% yield overall for steps 1-4).

[0095] Step 5 TIFF2026501779000035.tif301654-Cyano-2-fluoro-N-methylbenzamide compound (Formula IV, 1.0 equivalent) was charged to a reaction vessel along with SOCl (2.0 equivalents), DMF (0.1 equivalents), and toluene (6 volumes). The mixture was heated to between 75±5°C and stirred for 2 hours, then heated to 100±5°C and stirred for an additional 16 hours. The reaction mixture was concentrated to approximately 2.5 volumes. The mixture was redissolved in 6 volumes of toluene, concentrated to approximately 1.5 volumes, and then dissolved in DCM (3.5 volumes). The crude solution containing the compound of Formula V was used in the next step without further purification.

[0096] Step 6 A reaction vessel was charged with the compound of Formula III (Step 4, 1.0 equiv.), 2,6-lutidine (1.5 equiv.), and acetonitrile (5 vol.). The mixture was cooled to -10 ± 5 °C, and the crude DCM solution from Step 6 (1.05 equiv.) was added dropwise. 5% aqueous NaHCO3 (6 vol.) was added dropwise over 4 h, followed by stirring at -5 ± 5 °C for 1 h. The organic layer was separated, and the aqueous layer was washed with DCM (3.5 vol.). The combined organic layers were washed with 20% brine (6 vol.) and separated again. The crude solution containing the compound of Formula VI was used in the next step without further purification.

[0097] Step 7 The crude DCM solution from step 7 was charged with aqueous TsOH (0.05 equiv.) and concentrated under vacuum at 20 ± 5 °C to approximately 1.5 volumes, followed by the addition of toluene (7 volumes). The reaction mixture was heated to 90 ± 10 °C, stirred for 1.5 hours, and then cooled to 50 ± 10 °C. 5% aqueous NaHCO3 (6 volumes) was added dropwise over 6 hours, followed by stirring for 40 minutes. Water (6 volumes) was added dropwise over 4 hours, followed by stirring for an additional 40 minutes. The organic phase was separated, concentrated, and recrystallized from ethanol and water. The resulting crystals were filtered, washed with a mixture of ethanol and water, and dried in a vacuum oven at 50 °C to give compound of Formula XII as a brown solid (46.3% yield, 95.96% purity overall for steps 7–8).

[0098] Step 8 A mixture of Formula XII (Step 8) in DMSO (8 vol) was heated to 50±5°C and stirred for 1 hour. The mixture was cooled to 25±5°C and charged with K2CO3 (0.5 eq). 30% aqueous HO2 (1.5 eq) was added dropwise over 2 hours, followed by stirring for an additional 30 minutes. The reaction mixture was charged with 15.7% aqueous Na2SO3 (1.2 vol) and stirred for 1 hour. Soft water (6.5 vol) was then added and stirred for an additional 2-3 hours. The solid was filtered, washed with water, dried in a vacuum oven at 45±5°C, and recrystallized from a mixture of ethanol and water to give compound of Formula I as an off-white solid (87.8% yield, 99.73% purity).

[0099] Example 2 TIFF2026501779000039.tif62165

[0100] Step 1 A mixture of compound 201 (1.0 equiv.), tert-butyl carbazate (1.2 equiv.), HOBT (1.2 equiv.), EDC (1.2 equiv.), and triethylamine (1.5 equiv.) in DCM (5 vol.) was stirred at 25 ± 5 °C until completion. Water (8 vol.) was added to the reaction mixture and stirred for 10 min. The organic layer was separated and washed with 35% citric acid until the pH of the solution was between 6 and 7, 25% NaHCO3 until the pH of the solution was between 7 and 8, water, and concentrated. The crude solid containing compound 202 was used in the next step without further purification.

[0101] Step 2 A mixture of crude compound 202 (Example 2, Step 1, 1.0 equiv.), ethyl acetate (18 vol.), and a 4 M solution of HCl in ethyl acetate (34 equiv.) was stirred until completion at 25±5° C. The reaction mixture was concentrated, and the crude solid containing salt 203 was used in the next step without further purification.

[0102] Step 3 A mixture of crude salt 203 (Example 2, Step 2, 1.0 equiv.), 2,6-lutidine (2.5 equiv.), and dichloromethane (5 vol.) was charged to a flask and cooled to −10±5° C. A solution of Formula V in dichloromethane (1.1 equiv., 2.3 vol.) was added to the reaction mixture. The mixture was stirred at −10±5° C. for 16 hours. 3% aqueous NaHCO (40 vol.) was added to the reaction, which was then stirred at 10±5° C. for 1 hour. The mixture was filtered, the cake washed with water, and toluene (5 vol.) was charged to the cake. The resulting solution of compound 204 was used in the next step without further purification.

[0103] Step 4 A solution of compound 204 (Example 2, Step 3, 1.0 equiv.) was charged with p-toluenesulfonic acid monohydrate (0.05 equiv.), warmed to 95±5° C., and stirred for 60 h. The reaction mixture was filtered, the cake washed with toluene, and the resulting crude solid 205 was used in the next step without further purification.

[0104] Step 5 A mixture of crude compound 205 (Example 2, Step 4, 1.0 equiv.) and DMSO (10 vol.) charged with TIFF2026501779000044.tif34165K2CO3 (0.5 equiv.) was added to a round-bottom flask. 30% aqueous HO2 (3 equiv.) was added dropwise, followed by stirring at 15±5°C for 16 hours. 15.7% aqueous Na2SO3 (20 vol.) was added dropwise to the reaction mixture. The solid was filtered, washed with acetonitrile, dried in a vacuum oven at 45±5°C, reprecipitated from a mixture of DMF and water, filtered, and dried again to give compound of formula II as an off-white solid (91.51% purity).

[0105] Example 3 TIFF2026501779000045.tif24165

[0106] Step 1 A solution of compound of Formula VI (Example 1, Step 6, 1.0 equivalent) in dimethylacetamide was heated to 90±10° C. and stirred for 3 hours. The mixture was purified using column chromatography to give compound 301 in 10.04% yield and compound of Formula XII in 55.7% yield.

[0107] Step 2 A mixture of compound 301, DMSO (20 volumes), and KCO (0.5 equivalents) was added to a round-bottom flask. 30% aqueous HO (3 equivalents) was added dropwise and then stirred at 25±5°C for 20 hours. Water was added to the reaction mixture and stirred. The solid was filtered, washed with water, and dried in a vacuum oven at 45±5°C to give compound of formula XIII as an off-white solid (94.9% purity).

[0108] Example 4 TIFF2026501779000048.tif84165

[0109] Step 1 TIFF2026501779000049.tif38165 A mixture of compound of Formula IV (1.0 equiv.) in water (3 vol.) was charged to a round-bottom flask. Sulfuric acid (3 vol.) was added dropwise, and the mixture was heated to 90±10°C and stirred for 64 hours. Water (5 vol.) was added, and the solid was filtered and washed with water until the pH of the filtrate was between 5 and 7. The solid was dried at 50°C for 24 hours.

[0110] The solid intermediate was charged to a reactor along with toluene (10.5 vol) and thionyl chloride (3 eq). The mixture was heated to 75±5°C and stirred until clear, then stirred at 100°C for an additional 16 h. The mixture was concentrated and charged with acetonitrile (10 vol), then added to a mixture of acetonitrile (7 vol) and 40% aqueous methylamine (9 vol) and stirred at 25°C for 3 h. The mixture was adjusted to a pH between 6-7 with 6 M HCl, washed with ethyl acetate, concentrated, and recrystallized from ethanol to give compound 402, which was used in the next step without further purification.

[0111] Step 2 A solution containing compound 402 (1.0 equiv), DMF (0.1 equiv), thionyl chloride (3 equiv), and toluene (6 vol) was heated to 75±5° C. and stirred for 3 h, then heated to 100±5° C. and stirred for 16 h. The mixture was cooled to 55° C., concentrated, and charged with DCM (5 vol) to give a solution of compound 403, which was used in the next step without further purification.

[0112] Step 3 A reaction vessel was charged with the compound of Formula III (Example 1, Step 4, 1.0 eq.), 2.6-lutidine (1.5 eq.), and acetonitrile (5 vol.). The mixture was cooled to 5±5°C, and a crude DCM solution of 403 (1.05 eq.) was added dropwise and stirred for 16 hours. A 5% aqueous NaHCO3 solution (6 vol.) was added dropwise. The organic layer was separated, and the aqueous layer was washed with DCM (3.5 vol.). The combined organic layers were washed with water (6 vol.) and separated again. The crude solution containing compound 404 was used in the next step without further purification.

[0113] Step 4 TIFF2026501779000052.tif42165 A solution of compound 404 (Step 3, 1.0 equiv.) was charged with p-toluenesulfonic acid monohydrate (0.05 equiv.), concentrated, charged with toluene (3 vol.), warmed to 90±10°C, and stirred for 16 h. The reaction mixture was filtered, and the solid was charged with DCM and stirred until clear. The solution was washed with 5% NaHCO3, washed with water, concentrated, redissolved in hot ethanol, charged with water, filtered, and dried under vacuum to give compound of Formula XIV as a white solid (98.88% purity).

[0114] HPLC test method parameters for identity and impurity analysis The analytical testing procedure used to test compound identity and impurities employs reversed-phase HPLC with gradient elution. This method has been validated and shown to be stability indicative. Chromatographic separation was performed using a Waters Xterra RP18 column (150 × 4.6 mm, 5 μm, Waters Corporation, Milford, USA) and a Ghost-Sniper 4.6 × 50 mm ghost trap column at 40 °C.

[0115] The solvent mobile phase was (A) sodium phosphate buffer, pH 7.0, and (B) acetonitrile. Samples were dissolved in a 50:50 mixture of A and B with an injection volume of 20 μL and then separated at a flow rate of 1.0 mL / min using the following gradient profile: a linear change from (95% A, 5% B) to (30% A, 70% B) over 50 min, followed by (30% A, 70% B) for 10 min, and (95% A, 5% B) for 5 min. Compounds were detected at a wavelength of 220 nm.

[0116] Other embodiments The detailed description set forth above is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein should not be limited in scope by the specific embodiments disclosed herein, as these embodiments are intended as illustrations of some aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. Indeed, various modifications of the present disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description, which do not depart from the spirit or scope of the inventive findings. Such modifications are also intended to fall within the scope of the appended claims.

[0117] All references, patents (U.S. or foreign) or applications cited in this application are hereby incorporated by reference as if set forth in their entirety herein. In the event of any conflict, the content literally disclosed herein shall control.

Claims

1. Compounds of structural formula II: 。

2. Compounds of Formula XIII: 。

3. Compound of Formula XIV: 。

4. A compound of structural formula I: or a salt thereof, wherein the compound has an undetectable amount of formula II: A composition comprising:

5. A compound of structural formula I: or a salt thereof, in an amount of about 0.20% or less of a detectable amount of a compound of structural formula XIII: A composition comprising:

6. A compound of structural formula I: or a salt thereof, wherein the compound of formula XIV is present in an amount of about 0.20% or less. A composition comprising:

7. A pharmaceutical composition comprising the composition according to any one of claims 4 to 6 and a pharmaceutically acceptable carrier.

8. A method for treating an HSD-1 mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition according to any one of claims 4 to 6 or a pharmaceutical composition according to claim 7.

9. 10. A method for treating glucocorticoid excess or a condition thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 4 to 6 or the pharmaceutical composition of claim 7.

10. 10. The method of claim 9, wherein the glucocorticoid excess condition is Cushing's syndrome.

11. 10. The method of claim 9, wherein the state of glucocorticoid excess is autonomous cortisol secretion.

12. 10. The method of claim 9, wherein the glucocorticoid excess state is caused by the use of one or more glucocorticoid drugs.

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