Therapeutic compounds, formulations, and uses thereof

Abstract

The present disclosure provides a compound of formula (I) substantially free of impurities. [Formula 1] The present invention is directed, in part, to compositions comprising the compound of JPEG2025526320000067.jpg3858, processes for producing the same, and uses thereof.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 369,055, filed July 21, 2022, which is incorporated by reference herein in its entirety. Summary of the Invention

[0002] Disclosed herein, in certain embodiments, are compositions comprising compounds of formula (I) substantially free of impurities, processes for producing said compositions, and their uses, such as in treating, preventing, or reducing the risk or severity of a disease or disorder (e.g., cancer, fibrosis, and inflammatory diseases or disorders).

[0003] In one embodiment, a compound of formula (I):

[0004] [ka] Disclosed herein is a composition comprising a compound of formula (I), wherein the composition is substantially free of impurities.

[0005] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein the composition is substantially free of impurities.

[0006] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I), wherein the composition comprises no more than about 2% of a compound of formula (II).

[0007] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein the composition comprises no more than about 2% of a compound of formula (II).

[0008] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I), wherein the composition comprises no more than about 0.05% of a compound of formula (III).

[0009] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein the composition comprises no more than about 0.05% of a compound of formula (III).

[0010] In certain embodiments, provided herein are methods of treating cancer in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0011] In certain embodiments, provided herein are methods of treating fibrosis in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0012] In certain embodiments, provided herein are methods of treating an inflammatory disease or disorder in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0013] In certain embodiments, provided herein is a method of treating chemotherapy-induced peripheral neuropathy in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0014] In certain embodiments, provided herein are methods of treating diabetic neuropathy in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0015] In certain embodiments, provided herein are methods of treating familial amyloid polyneuropathy in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0016] In certain embodiments, provided herein are methods of treating cachexia in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0017] In certain embodiments, provided herein are methods of treating anaphylaxis in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0018] In certain embodiments, provided herein are methods of treating non-alcoholic fatty liver disease or steatohepatitis in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0019] In certain embodiments, provided herein is the use of the compositions disclosed herein to treat cancer in an individual in need thereof.

[0020] In certain embodiments, provided herein is the use of the compositions disclosed herein for treating fibrosis in an individual in need thereof.

[0021] In certain embodiments, provided herein is the use of a composition disclosed herein for treating an inflammatory disease or disorder in an individual in need thereof.

[0022] In certain embodiments, provided herein is a use of the compositions disclosed herein for treating chemotherapy-induced peripheral neuropathy in an individual in need thereof.

[0023] In certain embodiments, provided herein is the use of a composition disclosed herein for treating diabetic neuropathy in an individual in need thereof.

[0024] In certain embodiments, provided herein is the use of the compositions disclosed herein for treating familial amyloid polyneuropathy in an individual in need thereof.

[0025] In certain embodiments, provided herein is a use of the compositions disclosed herein for treating cachexia in an individual in need thereof.

[0026] In certain embodiments, provided herein is the use of a composition disclosed herein to treat anaphylaxis in an individual in need thereof.

[0027] In certain embodiments, provided herein is the use of a composition disclosed herein to treat anaphylaxis in an individual in need thereof.

[0028] In certain embodiments, provided herein is a use of a composition disclosed herein for treating non-alcoholic fatty liver disease or steatohepatitis in an individual in need thereof.

[0029] In an embodiment, disclosed herein is a method for assessing the purity of a composition comprising a compound of Formula (I), comprising assaying the composition for the presence of a compound selected from the group consisting of a compound of Formula (II), a compound of Formula (III), and a compound of Formula (IV).

[0030] In certain embodiments, disclosed herein are processes for preparing compounds of formula (I) that are substantially free of impurities.

[0031] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims. [Brief explanation of the drawings]

[0032] [Figure 1] A typical 1H-NMR spectrum of compound 7 in DMSO-d6 is shown. [Figure 2] A typical 13C-NMR spectrum of compound 7 in DMSO-d6 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0033] In an embodiment, the present disclosure provides a compound of formula (I) that is substantially free of impurities.

[0034] [ka] The present invention provides compositions comprising the compounds of formula (I), processes for producing the compositions, and methods for treating, preventing, or reducing the risk or severity of a disease or disorder (e.g., cancer, fibrosis, inflammatory disease or disorder) by administering the compositions.

[0035] definition As used herein, "a" or "an" can mean one or more. As used herein, when used with the word "comprising," "a" or "an" can mean one or more. As used herein, "another" can mean at least two or more. Furthermore, the terms "having," "including," "containing," and "comprising" are interchangeable, and those of skill in the art will recognize that these terms are open-ended terms. Some embodiments of the present disclosure can consist of, or consist essentially of, one or more components, method steps, and / or methods of the present disclosure. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein.

[0036] "About" and "approximately" are generally intended to mean an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0037] As used herein, "pharmaceutically acceptable salts" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, These include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0038] As used herein, "pharmaceutically acceptable excipient" refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient. Exemplary pharmaceutical excipients include those that aid in the manufacturing process, protect, support, or enhance stability, increase bioavailability, or increase patient acceptability. They may further aid in product identification or enhance the overall safety or function of the product during storage or use. The terms "excipient" and "carrier" are used interchangeably herein.

[0039] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," "subject," and "individual" are used interchangeably herein. None of these terms require the active supervision of a medical professional.

[0040] Disease, disorder, and illness are used interchangeably herein.

[0041] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" (also "therapeutic treatment") contemplate actions that occur while a subject is suffering from a specified disease, disorder, or condition, and that reduce the severity of the disease, disorder, or condition or reverse or slow the progression of the disease, disorder, or condition.

[0042] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, effective amounts of compounds of the present disclosure can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition (e.g., treating, preventing, and / or ameliorating cancer in a subject or inhibiting SH2 domain-mediated protein-protein interactions in a subject, at a reasonable benefit-to-risk ratio applicable to any medical treatment), or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent. "Prophylactic treatment" contemplates actions that occur before a subject begins to suffer from the specified disease, disorder, or condition.

[0043] The term "impurity" as used herein refers to a substance that is not the desired product (e.g., a compound of Formula (I)) or the intended pharmaceutically acceptable carrier or excipient in a composition. Exemplary impurities include, but are not limited to, synthetic impurities, intermediate impurities, isomers, oxides, hydrolysis products, dimerization products, and degradation products of a compound of Formula (I) and / or reactants or residual solvents used in the process of preparing a compound of Formula (I). Exemplary structures of such impurities (compounds of Formula (II), Formula (III), and Formula (IV)) are shown below:

[0044] [ka]

[0045] The term "substantially free" with respect to compositions described herein refers to a composition comprising a compound of Formula (I) that is free of at least a specified weight percent of one or more impurities, where the specified weight percent of the impurity is 30%, 25%, 20%, 15%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.005%, or any percentage between 0% and 1%, 0% and 2%, 0% and 5%, 0% and 10%, or 0% and 20%.

[0046] Ambient conditions of temperature as used herein refer to a temperature of about 15 to 30°C or about 20 to about 30°C, for example, about 20 to about 25°C.

[0047] composition When formulated into a pharmaceutical composition containing an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, certain impurities may be incompatible with other substances (e.g., the carrier) in the composition, reduce the shelf life of the composition, cause problems during formulation and use of the composition, cause physical and chemical instability of the composition, reduce the therapeutic efficacy of the composition, exhibit adverse biological effects, or alter the aroma, color, or taste of the composition. Compositions containing a compound of Formula (I) as described herein are, in some embodiments, synthesized and processed in a manner that produces a composition that is substantially free of impurities. Additionally, compositions containing a compound of Formula (I) as described herein are, in some embodiments, synthesized and processed to produce a sufficient quantity of the compound of Formula (I) (e.g., a manufacturing scale that produces, for example, 1 kg or more of the compound of Formula (I) per batch) while producing a composition that is substantially free of impurities.

[0048] In some embodiments, a compound of formula (I):

[0049] [ka] Disclosed herein is a composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of impurities.

[0050] In some embodiments, the impurity is a synthetic impurity, an intermediate impurity, an oxide, a hydrolysis product, a dimerization product, or a decomposition product of the compound of Formula (I). In some embodiments, the impurity is a reactant or residual solvent used in the process of preparing the compound of Formula (I).

[0051] In some embodiments, the impurity has formula (II):

[0052] [ka] is a compound of

[0053] In some embodiments, the impurity has formula (III):

[0054] [ka] is a compound of

[0055] In some embodiments, the impurity has formula (IV):

[0056] [ka] is a compound of

[0057] In some embodiments, the impurity is present in the composition at about 2% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 1% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.5% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.4% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.3% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.2% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.1% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.09% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.08% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.07% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.06% or less area by HPLC. In some embodiments, the impurity is present in the composition at about 0.05% or less area percent by HPLC. In some embodiments, the impurity is present in the composition at about 0.04% or less area percent by HPLC. In some embodiments, the impurity is present in the composition at about 0.03% or less area percent by HPLC. In some embodiments, the impurity is present in the composition at about 0.02% or less area percent by HPLC. In some embodiments, the impurity is present in the composition at about 0.01% or less area percent by HPLC. In some embodiments, the amount of impurity in the composition is undetectable by HPLC.

[0058] In some embodiments, the composition contains one or more impurities at about 2% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 1% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.5% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.4% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.3% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.2% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.1% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.09% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.08% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.07% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.06% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.05% or less by area by HPLC. In some embodiments, the composition contains one or more impurities at about 0.04% area percent by HPLC or less. In some embodiments, the composition contains one or more impurities at about 0.03% area percent by HPLC or less. In some embodiments, the composition contains one or more impurities at about 0.02% area percent by HPLC or less. In some embodiments, the composition contains one or more impurities at about 0.01% area percent by HPLC or less.

[0059] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains less than or equal to about 0.1% area percent by HPLC of one or more impurities after storing the composition at about 40° C. and about 75% relative humidity for about 6 months.

[0060] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains less than or equal to about 0.1% area percent by HPLC of one or more impurities after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0061] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains less than or equal to about 0.1% area percent by HPLC of one or more impurities after storing the composition at about 40° C. and about 75% relative humidity for about 2 months.

[0062] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains less than or equal to about 0.1% area percent by HPLC of one or more impurities after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0063] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0064] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 2 months.

[0065] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0066] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0067] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about two months.

[0068] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0069] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0070] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 2 months.

[0071] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 40° C. and about 75% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0072] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.3% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.2% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.1% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months.

[0073] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.3% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.2% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.1% area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months.

[0074] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less by area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months.

[0075] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storage of the composition at about 40° C. and about 75% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less by area by HPLC of one or more impurities after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months.

[0076] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less by area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less by area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less by area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about two months.

[0077] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.3% area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.2% area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains no more than about 0.1% area by HPLC of one or more impurities after storing the composition at about 25° C. and about 60% relative humidity for about 1 month.

[0078] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months.

[0079] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months.

[0080] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months.

[0081] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months.

[0082] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (II) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months.

[0083] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.3% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.2% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.1% or less of a compound of Formula (II) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month.

[0084] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months.

[0085] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months.

[0086] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months.

[0087] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months.

[0088] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about two months.

[0089] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.08% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.05% or less of a compound of Formula (III) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 1 month.

[0090] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 24 months. In some embodiments, a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 24 months.

[0091] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 12 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 12 months.

[0092] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 6 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 6 months.

[0093] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.5% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.4% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.3% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises about 0.2% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 3 months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 3 months.

[0094] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of a compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about two months. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 2 months.

[0095] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.5% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.4% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.3% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.2% or less of the compound of Formula (IV) by area percent by HPLC after storage of the composition at about 25° C. and about 60% relative humidity for about 1 month. In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, contains about 0.1% or less of the compound of Formula (IV) by area percent by HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 1 month.

[0096] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 2% by weight or less of a compound of Formula (II). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1.5% by weight or less of a compound of Formula (II). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1% by weight or less of a compound of Formula (II). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.5% by weight or less of a compound of Formula (II). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.1% by weight or less of a compound of Formula (II).

[0097] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 2% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1.5% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.5% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.1% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.09% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.08% or less by weight of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.07% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.06% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.05% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.04% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.03% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.02% by weight or less of a compound of Formula (III). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.01% by weight or less of a compound of Formula (III).

[0098] In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 2% by weight or less of a compound of Formula (IV). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1.5% by weight or less of a compound of Formula (IV). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 1% by weight or less of a compound of Formula (IV). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.5% by weight or less of a compound of Formula (IV). In some embodiments, a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises 0.1% by weight or less of a compound of Formula (IV).

[0099] Preparation method The compositions described herein are prepared using any of the methods described herein, for example, a composition of formula (I):

[0100] [ka] A composition comprising a compound of (a) Compound 2

[0101] [ka] Compound 1

[0102] [ka] Contact with compound 3

[0103] [ka] generating (b) contacting compound 3 with an oxidizing agent to form compound 4

[0104] [ka] generating (c) converting compound 4 to compound 5 in the presence of a coupling agent;

[0105] [ka] to produce a compound of formula (I), (d) contacting the compound of formula (I) of step (c) with an alcohol, water, or a combination thereof to form a mixture; and (e) filtering the mixture from step (d) to isolate the precipitate, wherein the precipitate is a composition comprising the compound of formula (I) substantially free of impurities. It is prepared by a process comprising:

[0106] In some embodiments, the oxidizing agent is periodate. In some embodiments, the oxidizing agent is sodium periodate or potassium periodate. In some embodiments, the coupling agent is boron trifluoride etherate.

[0107] In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, propanol, and hexanol, or mixtures thereof. In some embodiments, the alcohol is methanol. In some embodiments, the alcohol is ethanol. In some embodiments, the alcohol is isopropanol. In some embodiments, the alcohol is propanol. In some embodiments, the alcohol is hexanol.

[0108] In some embodiments, in step (d), the compound of Formula (I) in step (c) is contacted with a combination of an alcohol and water to form a mixture. In some embodiments, the alcohol is isopropanol.

[0109] In some embodiments, the process further comprises, after step (e), (f) dissolving the precipitate in a first solvent to form a mixture and washing the mixture with a wash solution selected from brine, water, and combinations thereof; and (g) separating the mixture of step (f) from the wash solution to obtain a separated mixture; optionally; (h) concentrating the separated mixture of step (g) to form a concentrated mixture. Further includes:

[0110] In some embodiments, the first solvent is selected from 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethyl sulfoxide, and methyl ethyl ketone, and mixtures thereof. In some embodiments, the first solvent is selected from 2-MeTHF and acetone. In some embodiments, the first solvent is 2-MeTHF.

[0111] In some embodiments, the process further comprises, after step (h), (i) contacting the concentrated mixture with a first solvent and adding charcoal to form a precipitate / charcoal mixture; (j) filtering the precipitate / charcoal mixture to form a filtrate; (k) adding a second solvent to the filtrate to form a second mixture comprising a second precipitate; and (l) filtering the second mixture to retain a second precipitate. Further includes:

[0112] In some embodiments, the process further comprises, after step (l), drying the second precipitate.

[0113] In some embodiments, the first solvent is selected from 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethyl sulfoxide, and methyl ethyl ketone, and mixtures thereof. In some embodiments, the first solvent is selected from 2-MeTHF and acetone. In some embodiments, the first solvent is acetone.

[0114] In some embodiments, the second solvent is pentane, hexane, or heptane, or a mixture thereof. In some embodiments, the second solvent is n-heptane.

[0115] In some embodiments, the process further comprises, after step (e), (f') dissolving the precipitate of the compound of formula (I) in a first solvent and adding charcoal to form a compound of formula (I) / charcoal mixture; (g') filtering the compound of Formula (I) / charcoal mixture to isolate a filtrate comprising the compound of Formula (I) (e.g., the filtration separates the charcoal from the filtrate comprising the compound of Formula (I)); (h') adding a second solvent to the filtrate of step (g') to form a second mixture containing a second precipitate comprising the compound of Formula (I); and (i') filtering the second mixture of step (h') to isolate a second precipitate comprising the compound of Formula (I). Further includes:

[0116] In some embodiments, the process further comprises, after step (i'), drying the second precipitate.

[0117] In some embodiments, the first solvent is selected from 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethyl sulfoxide, and methyl ethyl ketone, and mixtures thereof. In some embodiments, the first solvent is selected from 2-MeTHF and acetone. In some embodiments, the first solvent is acetone. In some embodiments, the first solvent is 2-MeTHF.

[0118] In some embodiments, the second solvent is pentane, hexane, or heptane, or a mixture thereof. In some embodiments, the second solvent is n-heptane.

[0119] In some embodiments, the impurity is an oxide of a compound of Formula (I), such as a compound of Formula (II). In some embodiments, the impurity is a synthetic impurity, such as a compound of Formula (III). In some embodiments, the impurity is a compound of Formula (IV). In some embodiments, the impurity is selected from the group consisting of a compound of Formula (II), a compound of Formula (III), and a compound of Formula (IV), or a combination thereof.

[0120] In some embodiments, the method produces 1 kg or more of a compound of Formula (I). In some embodiments, the method produces 2 kg or more of a compound of Formula (I). In some embodiments, the method produces 3 kg or more of a compound of Formula (I). In some embodiments, the method produces 4 kg or more of a compound of Formula (I). In some embodiments, the method produces 5 kg or more of a compound of Formula (I). In some embodiments, the method produces 10 kg or more of a compound of Formula (I). In some embodiments, the method produces 15 kg or more of a compound of Formula (I). In some embodiments, the method produces 20 kg or more of a compound of Formula (I). In some embodiments, the method produces 30 kg or more of a compound of Formula (I). In some embodiments, the method produces 40 kg or more of a compound of Formula (I). In some embodiments, the method produces 50 kg or more of a compound of Formula (I).

[0121] Formula (I):

[0122] [ka] Further disclosed herein is a method for evaluating a composition comprising a compound of the formula:

[0123] [ka] assaying the composition for the presence of a compound selected from the group consisting of:

[0124] In some embodiments, the assaying step comprises analysis using HPLC (High Performance Liquid Chromatography). In some embodiments, the assaying step comprises analysis using MS (Mass Spectrometry). In some embodiments, the assaying step comprises analysis using LC-MS (Liquid Chromatography Mass Spectrometry). In some embodiments, the assaying step comprises analysis using NMR (Nuclear Magnetic Resonance). In some embodiments, the assaying step comprises analysis using IR (Infrared Spectroscopy). In some embodiments, the assaying step comprises analysis using UV (Ultraviolet-Visible Spectroscopy). In some embodiments, the assaying step comprises analysis using a combination of HPLC, MS, LC-MS, NMR, IR, or UV.

[0125] In some embodiments, the method of evaluating a composition comprising a compound of Formula (I) comprises:

[0126] [ka] further comprising assaying for the amount of a compound selected from the group consisting of:

[0127] Pharmaceutical Compositions, Administration, and Dosages The compositions disclosed herein may further comprise pharmaceutically acceptable carriers, including, but not limited to, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared by any suitable method (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0128] The pharmaceutical compositions may be administered in either single or multiple doses by any of the generally accepted modes of administration for drugs having similar utilities as described in the patents and patent applications incorporated by reference, including, for example, rectal, oral, intranasal, and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, or a cylindrical polymer for arterial insertion.

[0129] One mode of administration is parenteral, particularly by injection. For administration by injection, the compositions of the present disclosure may be incorporated into aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also commonly used for injections. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0130] Sterile injectable solution can be prepared by incorporating the composition of the present disclosure in the required amount into a suitable solvent together with various other ingredients listed above, and then optionally filter sterilization can be carried out.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and other necessary ingredients listed above.For the preparation of sterile injectable solution, the preferred method for preparing sterile powder is vacuum drying and freeze-drying technology, which can obtain the powder of active ingredient and any additional desired ingredients from the solution that has been previously sterilized by filtering.

[0131] Oral administration is another route of administration for the compositions of the present disclosure. Administration may be via capsules or enteric-coated tablets, etc. When preparing pharmaceutical compositions containing the compounds described herein, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile-packaged powders.

[0132] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents, and flavoring agents.

[0133] The compositions disclosed herein can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to a patient by utilizing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and elution systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

[0134] In some embodiments, compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for single dosage administration in human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compositions are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably 0.1 to 1000 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician, taking into account relevant circumstances, including the disease being treated, the selected route of administration, the composition actually administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0135] When preparing solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0136] The tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of a membrane covering the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0137] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by using inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0138] In some embodiments, the composition comprising the compound of Formula (I) is administered to a subject as an oral dosage form. In some embodiments, the oral dosage form is in the form of a tablet. In some embodiments, the oral dosage form is in the form of a capsule.

[0139] The dosage may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in consideration of the patient's condition. (See, e.g., Fingl et al., 1975, "The Pharmacological Basis of Therapeutics"). Lower or higher doses than those described above may be required. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder, or condition, the subject's predisposition to the disease, disorder, or condition, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of the compounds as described herein.

[0140] How to use In certain embodiments, also provided herein are methods of using a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the methods of treatment or other methods described herein, wherein the composition is substantially free of impurities.

[0141] In some embodiments, the method comprises administering a compound of Formula (I), i.e., a STAT3 inhibitor, wherein the compound of Formula (I) is formulated in a manner described herein (e.g., present in a composition as described herein). In some embodiments, a compound of Formula (I) (e.g., as formulated herein, e.g., as an oral dosage form) is utilized in a method for treating, preventing, or reducing the risk or severity of a disease or disorder mediated by STAT3 or a potential disease or disorder treatable by a STAT3 inhibitor. For example, the compositions described herein are useful for treating, preventing, or reducing the risk or severity of a disease or disorder characterized by excessive STAT3 protein expression. In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of cancer. In other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of fibrosis. In yet other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder.

[0142] Signal Transducer and Activator of Transcription 3 (STAT3) is central to the regulation of anti-tumor immune responses. STAT3 is widely overactivated in both cancer and non-cancer cells within the tumor ecosystem, where it plays a key role in inhibiting the expression of critical immune activation regulators and promoting the production of immune suppressive factors. The methods provided herein are intended to be useful for the treatment of cancers, including, for example, solid tumors, soft tissue tumors, and their metastases.

[0143] In some embodiments, the present invention provides a method for treating, preventing, or reducing the risk or severity of cancer in an individual in need thereof, comprising administering any of the compositions described herein to the individual. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, osteosarcoma, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor-positive breast cancer. In some embodiments, the cancer treated in accordance with the methods provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer. In some embodiments, the leukemia is acute myeloid leukemia.

[0144] In some embodiments, a method for treating cancer in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein. In some embodiments, the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, bone tumor, spleen cancer, gallbladder cancer, stomach cancer, anal cancer, post-transplant lymphoproliferative disease, restenosis, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain tumor, pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, or metastatic melanoma. In some embodiments, the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer.

[0145] Furthermore, STAT3 is important for Th17 lymphocyte development and cytokine production, and its activation is associated with the development of airway inflammation. Upon activation, STAT3 is recruited to the cytokine-activated receptor complex and becomes phosphorylated at Tyr(Y)705. Phosphotyrosylated (p)STAT3 homodimerizes through SH2-pY705 interactions, translocates to the nucleus, and binds to promoters, transcriptionally activating genes that drive Th17 differentiation and the production of multiple cytokines. STAT3 activation is also involved in Th2 cytokine production, making it an attractive target for the treatment of asthma. In addition, several genes, including ATG16L, NOD2 / CARD15, IBD5, CTLA4, TNFSF15, JAK2, STAT3, IL23R, and ORMDL3, have been implicated as risk factors for inflammatory bowel disease (IBD) in genome-wide association studies (GWAS). These genes implicate antimicrobial peptides, innate and adaptive immune cell function, Th17 cells, regulatory T cells (Tregs), and cytokines (tumor necrosis factor, interleukin-17, -23, -12, -22, and IL-6). Many of these cytokines act as ligands for cell surface receptors that activate STAT3. STAT3 expression in three cell lineages—myeloid cells, enterocytes, and T cells—contributes to colitis in mice and humans. Therefore, targeting STAT3 represents an effective means of treating, preventing, or reducing the risk or severity of inflammatory diseases / disorders.

[0146] In some embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder in an individual in need thereof, the methods comprising administering any of the compositions described herein to the individual. In some embodiments, the inflammatory disease / disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, nonalcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis, multiple sclerosis, or pancreatitis. In some embodiments, the inflammation treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, or nonalcoholic steatohepatitis (NASH). In some embodiments, anaphylaxis includes anaphylactic shock.

[0147] In some embodiments, there is provided a method of treating non-alcoholic fatty liver disease or steatohepatitis in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0148] In some embodiments, methods are provided for treating an inflammatory disease or disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein, in some embodiments, the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, sclera, multiple sclerosis, pancreatitis, or asthma.

[0149] Fibrosis is a pathological process involving the accumulation of excess extracellular matrix in tissues, resulting in tissue damage and organ dysfunction, which can progress to organ failure and death. In systemic sclerosis, an idiopathic fibrotic disease, the trigger is hypothesized to be an autoimmune response leading to tissue injury, production of growth factors, pro-inflammatory and pro-fibrotic cytokines, and accumulation of myofibroblasts. Two potential sources of myofibroblasts are local fibroblast differentiation and the process of epithelial-mesenchymal transition (EMT). IL-6 is a pro-inflammatory and pro-fibrotic cytokine that is increasingly recognized as a key mediator of fibrosis, contributing to myofibroblast accumulation. After binding to its receptor, IL-6 signals through STAT3. Therefore, STAT3 is a potentially important protein target for treating fibrosis.

[0150] In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis in an individual in need thereof, the methods comprising administering to the individual any of the compositions described herein. In certain embodiments, the fibrosis is associated with a disorder or disease such as skin fibrosis (or dermal fibrosis), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal space, renal fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or localized systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis. In certain embodiments, the fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal space, bone marrow fibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, the fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, cirrhosis, or pulmonary fibrosis.

[0151] In some embodiments, methods of treating fibrosis in an individual in need thereof are provided, the methods comprising administering to the individual a therapeutically effective amount of a composition disclosed herein. In some embodiments, the fibrosis is associated with pulmonary fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, hepatic fibrosis, retroperitoneal fibrosis, myelofibrosis, renal fibrosis, bone marrow fibrosis, dermal fibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In some embodiments, the fibrosis is associated with pulmonary fibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

[0152] In certain embodiments, the fibrosis is associated with fibrosis following exposure to certain drugs such as chemotherapy, exposure to environmental or other toxins or allergens, fibrosis occurring after ischemia / reperfusion injury such as myocardial infarction or hypotension, fibrosis occurring after radiation, fibrosis following hepatitis induced by alcohol, toxins, drugs, or infection, fibrosis following primary biliary cirrhosis, viral infections involving the heart, liver, or lungs, and / or idiopathic retroperitoneal fibrosis.

[0153] Muscle wasting is a debilitating complication of catabolic conditions, including chronic kidney disease (CKD), diabetes, cancer, or severe infection. For example, in mice with CKD, myostatin inhibition reduced circulating levels of IL-6 and TNFα, suggesting a relationship between inflammation and muscle wasting, as reported in clinical studies. STAT3 was found to be activated by the IL-6 family of cytokines, thus suggesting that the STAT3 pathway is related to muscle mass loss.

[0154] In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of a muscle-wasting disease / disorder, a muscle-weakness disease / disorder, or cachexia in an individual in need thereof, the methods comprising administering any of the compositions described herein to the individual. The muscle weakness and / or muscle wasting and / or cachexia may have an unknown cause or may be associated with an underlying disease. The underlying condition may be a catabolic condition. In some embodiments, the underlying condition associated with cachexia is minimal renal disease or failure, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormone deficiency, metabolic acidosis, infection, chronic pancreatitis, autoimmune disorders, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever, long bone fractures, thoracic aneurysm ... Hypergonadism, long-term steroid therapy, surgery, bone marrow transplant, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, paraneoplastic syndromes, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dermatomyofibrosis, rheumatic disease, autoimmune disease, collagen vascular disease, visceral leishmaniasis, and / or addiction to drugs such as amphetamines, opiates, or barbiturates.

[0155] In some embodiments, a method of treating cachexia in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0156] Additionally, STAT3 signaling is involved in gap junction intercellular communication, IL-6- and IL-11-induced vascular leakage, VE-cadherin downregulation concomitant with STAT3 phosphorylation, and STAT3 / mir17-92 / E2F1-dependent regulation of β-catenin nuclear translocation and transcriptional activity. Therefore, STAT3 inhibition is useful for reducing vascular permeability in the setting of anaphylaxis.

[0157] In some embodiments, a method of treating anaphylaxis in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0158] In some embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of an allergic reaction in an individual in need thereof, the methods comprising administering any of the compositions described herein to the individual. In some embodiments, the allergic reaction is induced after exposure to an allergen. In some embodiments, the allergen is a food allergen (such as milk, legumes, shellfish, nuts, eggs, fish, soybeans, and wheat), an environmental or seasonal allergen (such as pollen or mold), a venom allergen (such as from hornets, wasps, ants, Asian giant hornets, Japanese black hornets, or Egyptian cobras), a drug allergen (such as anesthetics, beta-lactam antibiotics), aspirin, nonsteroidal anti-inflammatory drugs, chemotherapy, vaccines, protamine, or herbal medicines), or latex. In some embodiments, the allergic reaction is anaphylaxis, anaphylactic shock, allergic rhinitis, hives, food allergy, drug allergy, hymenoptera allergy, bronchoconstriction, asthma, or eczema.

[0159] STAT3 also plays an important role in viral infection and pathogenesis. In some embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of a viral infection in an individual in need thereof, the method comprising administering any of the compositions described herein to the individual. In some embodiments, the viral infection is a chronic viral infection. In some embodiments, the chronic viral infection is AIDS, HIV infection, hepatitis B infection, hepatitis C virus infection, or Epstein-Barr virus infection.

[0160] In addition, reactive astrocytes in neurodegenerative diseases, including Alzheimer's disease, are involved in STAT3 phosphorylation. The pathophysiological role of astrocytes in a reactive state is believed to have important significance in the pathogenesis of neurodegenerative diseases. In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of a neurodegenerative disease in an individual in need thereof, the methods comprising administering to the individual any of the compositions described herein. In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemobrain. In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of pain in an individual in need thereof, the methods comprising administering to the individual any of the compositions described herein. In some embodiments, the pain is neuropathic pain. In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagas cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

[0161] In some embodiments, methods are provided for treating a neurodegenerative disease or disorder in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a composition disclosed herein. In some embodiments, methods are provided for treating chemotherapy-induced peripheral neuropathy in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a composition disclosed herein. In some embodiments, methods are provided for treating diabetic neuropathy in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a composition disclosed herein. In some embodiments, methods are provided for treating familial amyloid polyneuropathy in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0162] STAT3 is involved in cytokine-induced and nutrient-induced insulin resistance, and excessive STAT3 signaling contributes to the development of insulin resistance, such as skeletal muscle insulin resistance in type 2 diabetes. In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of insulin resistance in an individual in need thereof, comprising administering to the individual any of the compositions described herein. In some embodiments, the insulin resistance is the result of an underlying disease. In some embodiments, the insulin resistance is associated with the muscle of the individual being treated. In some embodiments, the insulin resistance is caused by any reason in the individual, such as elevated free fatty acids in the blood, obesity, overweight, having visceral fat, high fructose intake, inflammation, inactivity, gut microbiota dysbiosis, and / or genetic predisposition. In some embodiments, any of the methods provided herein are methods for treating, preventing, or reducing the risk or severity of a medical condition associated with insulin resistance or a medical condition that is at least partially a complication of insulin resistance, such as severe hyperglycemia, severe hypoglycemia, heart attack, stroke, kidney disease (including chronic, e.g., chronic kidney disease (CKD)), eye problems, cancer, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), metabolic syndrome, diabetes, or Alzheimer's disease. In some embodiments, insulin resistance is a characteristic of metabolic syndrome and type 2 diabetes. Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Symptoms include high blood triglycerides, blood pressure, abdominal fat, and blood sugar, as well as low levels of HDL (good) cholesterol.

[0163] In some embodiments, there is provided a method of treating non-alcoholic fatty liver disease or steatohepatitis in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0164] In some embodiments, the method comprises administering to an individual a therapeutically effective amount of a composition disclosed herein. In certain embodiments, the method comprises administering to an individual at least 1 mg / kg / day of a compound of Formula (I). In certain embodiments, the method comprises administering to an individual at least 10 mg / kg / day of a compound of Formula (I). In certain embodiments, the method comprises administering to an individual at least 20 mg / kg / day of a compound of Formula (I). In certain embodiments, the method comprises administering to an individual at least 25 mg / kg / day of a compound of Formula (I). [Example]

[0165] Exemplary HPLC conditions were: diluent was 0.1% trifluoroacetic acid (TFA) in acetonitrile, mobile phase A was 0.05% TFA in water, and mobile phase B was 0.05% TFA in acetonitrile; column (Agilent, Eclipse XDB-C18, 3.0 × 100 mm, 1.8 μm particle size), flow rate (0.425 mL / min), and detector (280 nm diode array).

[0166] Example 1. Synthesis of TTI-101

[0167] [ka]

[0168] Method 1 A mixture of 4-aminonaphthalen-1-ol HCl salt (281 g, 1.44 mol), sodium acetate (358 g, 4.35 mol), 4-methoxybenzenesulfonyl chloride (330 g, 1.60 mol), and purified water (5.4 L) was stirred and heated at 80 °C for approximately 5 hours. After the mixture was cooled to room temperature, the resulting solid was collected by filtration and washed with water. The solid was dried to give compound 3 (466 g, 98.5% yield).

[0169] To a solution of sodium periodate (105 g) in water (466 g), dichloromethane (DCM) (7 L) and silica gel (830 g) were added and the mixture was stirred. Compound 3 (451 g) in DCM (1.4 L) was added to the mixture and stirred for 6 hours. Sodium sulfate (707 g) was then added to the mixture and stirred for 2 hours. The mixture was filtered and rinsed with DCM. 2-Naphthol (200 g) and boron trifluoride diethyl etherate (8 mL, 0.06 mol) were added to the mixture and stirred at 38 °C for approximately 0.5 hours. Additional boron trifluoride diethyl etherate (8 mL, 0.06 mol) was added to the mixture and stirred at 38 °C for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, and dried under reduced pressure to give TTI-101 (616 g, 95.3% yield, 99.5% purity by HPLC). The collected solid was dissolved in acetone (4.5 L). Activated carbon (123 g) was added to the solution, stirred for approximately 2 hours, and filtered over Celite®. n-Heptane (8 L) was then added to the combined filtrate, stirred, and allowed to stand overnight to give a slurry. The slurry was filtered, and the solid was dried under pressure for 18 hours to give TTI-101 (556 g, 86.0% overall yield, 99.8214% purity by HPLC). HPLC analysis further showed compound 6 at 0.1111% AUC and compound 7 at approximately 0.02% AUC:

[0170] [ka]

[0171] Method 1-a: TTI-101 (10.03 g) from Method 1 above was combined with acetone (40 mL) under nitrogen with stirring. Additional acetone (33 mL) was added to the mixture while heating to 53 °C with a mantle and stirring to dissolve the solids. Heptane (55 mL) was added portionwise with stirring, and the resulting slurry was cooled to 22 °C, then further cooled at 4–5 °C. The slurry was filtered through a funnel under reduced pressure with chilled solvent (1:1 acetone and heptane) to complete the transfer of the solids to the funnel and wash the solids. The solids were dried under reduced pressure without heating. The purity of the isolated solid (80.8% recovery) was determined by HPLC to be 99.8445% AUC, with compound 6 at 0.1047% AUC.

[0172] Method 1-b: TTI-101 (9.82 g) from Method 1 above was combined with 1:1 acetone and heptane (100 mL) under nitrogen with stirring at ambient temperature, then cooled in an ice / water bath. The resulting slurry was filtered through a funnel under reduced pressure using chilled solvent (1:1 acetone and heptane) to complete the transfer of the solid to the funnel and wash the solid. The solid was dried under reduced pressure without heating. The purity of the isolated solid (82.5% recovery) was determined by HPLC to be 99.8404% AUC, with Compound 6 at 0.0982% AUC.

[0173] Method 2 A 5 kg batch of TTI-101 was synthesized using similar synthetic steps as described in Method 1. HPLC analysis showed that the API product contained approximately 2% AUC of compound 7. The batch also contained compound 6 prior to the recrystallization and / or slurrying methods in Table 1.

[0174] Table 1 lists exemplary recrystallizations and / or slurrying of TTI-101 from batches obtained according to Method 2.

[0175] [Table 1-1]

[0176] [Table 1-2]

[0177] [Table 1-3]

[0178] [Table 1-4]

[0179] [Table 1-5]

[0180] Method 3 A mixture of 4-aminonaphthalen-1-ol HCl salt (5.0 kg, 25.6 mol), potassium acetate (7.5 kg, 76.8 mol), 4-methoxybenzenesulfonyl chloride (5.8 kg, 28.2 mol), and purified water (75 kg) was stirred and heated at 80° C. for 2 hours. After the mixture was cooled to room temperature, the resulting solid was collected by filtration and washed with water. The solid was dried to give compound 3 (7.79 kg, 92.7% yield).

[0181] A solution of sodium periodate (1.9 kg) in water (34 kg) was added to a mixture of compound 3 (7.0 kg) in DCM (139 kg). The resulting mixture was stirred at 20°C for 1 hour and held at 25°C for 3 hours. The layers were separated, and the organic layer was washed twice with brine. The mixture was vacuum distilled twice, diluted with DCM (70 L), and then distilled to a final volume of 70 L. To this mixture was added 2-naphthol (3.4 kg) and a solution of boron trifluoride dibutyl etherate (40.19 g) in DCM (10 L) and stirred for 6.5 hours. The reaction mixture was quenched with 70% wet IPA (7 L). The resulting solid was collected, dissolved in 2-MeTHF (105 L), and washed with 10% brine (2 x 35 L) and water (1 x 35 L). The mixture was concentrated and charged with acetone. The resulting mixture was loaded onto activated carbon and stirred for 12 hours. The mixture was filtered over Celite® (diatomaceous earth) and concentrated. N-heptane was added to the mixture, which was stirred at 45°C for 2 hours, cooled to 25°C, and stirred for 12 hours. The resulting solid was filtered, washed with a mixture of acetone / n-heptane, then n-heptane, and then dried to give TTI-101 (6.46 kg, 64.6% yield, 99.95% purity). No formation of compound 7 was detected.

[0182] Another batch of TTI-101 was prepared according to Method 3 above, yielding 17.5 kg of TTI-101. No formation of compound 7 was detected. The purity of TTI-101, as determined by HPLC, averaged 99.8%, with compound 6 at 0.13% AUC.

[0183] Another batch of TTI-101 was prepared according to Method 3 above, yielding 40.0 kg of TTI-101. No formation of compound 7 was detected. The purity of TTI-101, as determined by HPLC, averaged 100.0%, with compound 6 at 0.05% AUC.

[0184] Another batch of TTI-101 was prepared according to Method 3 above, yielding 17.4 kg of TTI-101. No formation of compound 7 was detected. The purity of TTI-101, as determined by HPLC, averaged 99.9%, with compound 6 at 0.09% AUC.

[0185] Method 4 A batch of TTI-101 (6.4 kg) from Method 3 was dissolved in 2-MeTHF, warmed to 50°C, then cooled to 35°C and transferred through an in-line filter (0.45 microns) to a reactor containing n-heptane over 4 hours. The resulting slurry was adjusted to 25±5°C and stirred at 25±5°C for 12 hours. The slurry was filtered, and the solid was washed with n-heptane (21.9 kg). The solid was dried and delumped to give TTI-101 (5.89 kg, 92.0% yield, 99.76% purity). No formation of compound 7 was detected.

[0186] Method 5 A mixture of 4-aminonaphthalen-1-ol HCl salt (5.0 kg, 25.6 mol), potassium acetate (7.5 kg, 76.8 mol), 4-methoxybenzenesulfonyl chloride (5.8 kg, 28.2 mol), and purified water (75 kg) was stirred and heated at 80° C. for 2 hours. After the mixture was cooled to room temperature, the resulting solid was collected by filtration and washed with water. The solid was dried to give compound 3 (7.78 kg, 92.6% yield).

[0187] A solution of sodium periodate (1.8 kg) in water (34 kg) was added to a mixture of compound 3 (7.0 kg) in DCM (139 kg). The resulting mixture was stirred at 20° C. for 1 hour and maintained at 25° C. for 3 hours. The reaction mixture was filtered through Celite® and washed with DCM. The layers were separated, and the organic layer was washed twice with brine. The mixture was vacuum distilled twice, diluted with DCM (70 L), and then distilled to a final volume of 70 L. To this mixture was added 2-naphthol (3.4 kg) and a solution of boron trifluoride dibutyl etherate (61.0 g) in DCM (10 L) and stirred for 6 hours. The reaction mixture was quenched with 70% wet IPA (7 L). The resulting solid was collected, washed with DCM, and dried. The solid was dissolved in 2-MeTHF (105 L) and washed with 10% brine (2 x 35 L) and water (1 x 35 L). The resulting mixture was loaded onto activated carbon and stirred for 12 hours. The mixture was filtered over Celite® and concentrated. The filtrate was added to n-heptane and stirred at 25°C for 12 hours. The resulting solid was filtered, washed with n-heptane, and then dried to give TTI-101 (5.85 kg, 58.5% yield, 99.42% purity). No formation of compound 7 was detected.

[0188] Example 2. Synthesis of Compound 7 Method A. TTI-101 (0.52 g) and boron trifluoride etherate (0.13 mL) were stirred in DCM (25 mL) under nitrogen at 38° C. for about 16.5 hours and at ambient temperature for about 3 days. The resulting slurry was filtered under reduced pressure and washed with DCM. The solid was dried under reduced pressure at 42° C. HPLC analysis showed 1.93% conversion to compound 7.

[0189] Method B. TTI-101 (0.51 g) and boron trifluoride etherate (0.33 mL) were stirred in acetonitrile (25 mL) under nitrogen at 50 °C for approximately 4 days, and at the 30 hour mark, additional boron trifluoride etherate (0.20 mL) was added. The resulting slurry was cooled to ambient temperature, filtered under reduced pressure, and washed with acetonitrile. The solid was dried under reduced pressure at 50 °C to 55 °C. HPLC analysis indicated compound 7 with a purity of 99.87% AUC. The H-NMR and C-NMR spectra of the product are shown in Figures 1 and 2, respectively.

[0190] Example 3. Accelerated and low temperature stability studies of TTI-101 Batch A was similarly prepared using Method 3 described in Example 1. Batch B was prepared according to Method 5 described in Example 1.

[0191] Long-term stability of batch A Samples of TTI-101 were stored at 5°C, 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH. TTI-101 was stored in an LDPE bag closed with a nylon cable tie, then transferred to another LDPE bag closed with a nylon cable tie. The contents were placed in an HDPE bottle and closed with a polyethylene-lined polypropylene cap. Samples were stored under the conditions indicated above.

[0192] Long-term stability of batch B Samples of TTI-101 were stored at 5°C, 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH. TTI-101 was stored in an LDPE bag closed with a nylon cable tie, then transferred to another LDPE bag closed with a nylon cable tie. The contents were placed in an HDPE bottle and closed with a polyethylene-lined polypropylene cap. Samples were stored under the conditions indicated above.

[0193] The samples were analyzed using HPLC under the exemplary conditions shown above. The relative retention times (RRT) were about 0.83 for compound 5, about 1.05-1.06 for compound 4, about 1.15-1.17 for compound 6, and about 0.99 for the compound of formula (IV).

[0194] Abbreviation: NA Not applicable NQ 0.02% or more and 0.05% or less Avg Average Cmpd compound - No peaks M month RRT Relative Retention Time

[0195] For Batch A: a) Storage conditions: 5℃:

[0196] [Table 2-1]

[0197] [Table 2-2]

[0198] b) 25℃ / 60%RH:

[0199] [Table 3-1]

[0200] [Table 3-2]

[0201] c) 40℃ / 75%RH:

[0202] [Table 4]

[0203] For Batch B: a) Storage conditions: 5℃:

[0204] [Table 5-1]

[0205] [Table 5-2]

[0206] b)Storage conditions: 25℃ / 60%RH:

[0207] [Table 6-1]

[0208] [Table 6-2]

[0209] Storage conditions: 40°C / 75%RH

[0210] [Table 7]

[0211] Based on the stability studies for Batch A and Batch B described above, Batch A demonstrated excellent stability over a 24 month period.

[0212] 3-month stability data for batches B, C, D, and E Batches B, C, and D were prepared according to Method 5, Method 4, and Method 3, respectively, as described in Example 1. Batch E was similarly prepared according to Method 1 as described in Example 1.

[0213] Samples of TTI-101 (Batches B, C, D, and E) were stored at 40°C / 75% RH for 3 months. Batches were individually stored in low-density polyethylene (LDPE) bags closed with nylon cable ties, then transferred to another LDPE bag closed with a nylon cable tie. The contents were placed in high-density polyethylene (HDPE) bottles and closed with polyethylene-lined polypropylene caps. For batch B only, another sample was placed in an amber glass bottle with a screw cap and closed with a cap. The samples were stored under the conditions indicated above.

[0214] T=0 months (0M)

[0215] [Table 8]

[0216] T=1 month (1M)

[0217] [Table 9]

[0218] T=2 months (2M)

[0219] [Table 10]

[0220] T=3 months (3M)

[0221] [Table 11]

[0222] Storage conditions: 40°C / 75% relative humidity (RH): Batch C:

[0223] [Table 12]

[0224] Batch D:

[0225] [Table 13]

[0226] Batch B (stored in LDPE):

[0227] [Table 14]

[0228] Batch B (stored in glass):

[0229] [Table 15]

[0230] Batch E:

[0231] [Table 16]

Claims

1. a) Formula (I): 【Chemistry 1】 The compound and b) Compounds of formula (II), compound (III), and compound (IV): 【Chemistry 2】 Or an impurity selected from the group consisting of combinations thereof, which is present in the composition at an area ratio of 2% or less by high-performance liquid chromatography (HPLC) and A composition containing the following:

2. (a) Equation (I): 【Transformation 3】 The compound and b) Compounds of formula (II), compound (III), and compound (IV): 【Chemistry 4】 An impurity selected from the group consisting of or combinations thereof, which is present in the composition at an area ratio of 2% or less by high-performance liquid chromatography (HPLC), (c) A pharmaceutically acceptable carrier and A composition containing the following:

3. The composition according to claim 1 or 2, wherein the impurity is present in the composition at an area ratio of about 1% or less as determined by HPLC.

4. The composition according to claim 1 or 2, wherein the impurity is present in the composition at an area ratio of about 0.5% or less as determined by HPLC.

5. The composition according to claim 1 or 2, wherein the impurity is present in the composition at an area ratio of about 0.1% or less as determined by HPLC.

6. The composition according to claim 1 or 2, wherein the impurity is present in the composition at an area ratio of about 0.05% or less as determined by HPLC.

7. The composition according to claim 1 or 2, wherein the amount of impurities is undetectable by HPLC.

8. The composition according to claim 1 or 2, for use in treating cancer in individuals requiring treatment.

9. The composition according to claim 8, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, bone tumor, spleen cancer, gallbladder cancer, stomach cancer, anal cancer, post-transplant lymphoproliferative disorder, restenosis, ovarian cancer, multiple myeloma, prostate cancer, cervical cancer, brain tumor, pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, or metastatic melanoma.

10. The composition according to claim 1 or 2, for use in treating fibrosis in individuals requiring treatment.

11. The composition according to claim 10, wherein the fibrosis is related to pulmonary fibrosis, intestinal fibrosis, pancreatic fibrosis, arthral fibrosis, hepatic fibrosis, retroperitoneal fibrosis, myelofibrosity, renal fibrosis, bone marrow fibrosis, cutaneous fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

12. The composition according to claim 1 or 2 for use in treating an inflammatory disease or disorder, chemotherapy-induced peripheral neuropathy, diabetic neuropathy, familial amyloid polyneuropathy, cachexia, anaphylaxis, non-alcoholic fatty liver disease, or steatohepatitis in an individual requiring treatment.

13. Formula (I): 【Transformation 5】 A method for evaluating the purity of a composition containing the compound, 【Transformation 6】 A method comprising the step of assaying the composition for the presence of a compound selected from the group consisting of the following.

14. The method according to claim 13, wherein the assay step includes analysis using HPLC. 【Request Item 15】 【Chemistry 7】 The method according to claim 13, further comprising the step of assaying the amount of a compound selected from the group consisting of the following.

16. a) Formula (I): 【Transformation 8】 The compound and b) Compounds of formula (II), compound (III), and compound (IV): 【Chemistry 9】 Or an impurity selected from the group consisting of combinations thereof, which is present in the composition at an area ratio of 2% or less by high-performance liquid chromatography (HPLC) and A process for preparing a composition comprising, (a) Compound 2: 【Chemistry 10】 of Compound 1: 【Chemistry 11】 Make contact with it, Compound 3: 【Chemistry 12】 The process of generating (b) Compound 3 is brought into contact with an oxidizing agent, and compound 4: 【Chemistry 13】 The process of generating (c) Compound 4 is converted to Compound 5 in the presence of a coupling agent: 【Chemistry 14】 A step of bringing it into contact with the crude compound of formula (I), (d) A step of contacting the crude compound of formula (I) from step (c) with an alcohol, water, or a combination thereof to form a mixture, and (e) A step of filtering the mixture from step (d) to isolate a precipitate, wherein the precipitate is a compound of formula (I) that is substantially free of impurities. A process that includes this.

17. The process according to claim 16, wherein the oxidizing agent is a periodate (for example, sodium periodate or potassium periodate).

18. The process according to claim 16, wherein the coupling agent is boron trifluoride etherate.

19. The process according to claim 16, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, propanol, and hexanol.

20. The process according to claim 19, wherein the alcohol is isopropanol.

21. The process according to claim 16, wherein in step (d), the crude compound of formula (I) from step (c) is brought into contact with a combination of alcohol and water to form the mixture.

22. After step (e) of claim 16, (f) Dissolving the precipitate in a first solvent to form a mixture, washing the mixture with a washing solution selected from brine, water, and combinations thereof, and (g) Separating the mixture from step (f) from the washing solution to obtain the separated mixture, and optionally, (h) A step of concentrating the separated mixture from step (g) to form a concentrated mixture. The process according to claim 16, further comprising:

23. After step (h) of claim 22, (i) A step of contacting the concentrated mixture with a first solvent and adding charcoal to form a precipitate / charcoal mixture, (j) A step of filtering the precipitate / charcoal mixture to form a filtrate, (k) A step of adding a second solvent to the filtrate to form a second mixture containing a second precipitate, and (l) The second mixture is filtered to retain the second precipitate. The process according to claim 22, further comprising:

24. After step (e) of claim 16, (f') A step of dissolving the precipitate in a first solvent and adding charcoal to form a precipitate / charcoal mixture, (g') A step of filtering the precipitate / charcoal mixture to form a filtrate, (h') A step of adding a second solvent to the filtrate to form a second mixture containing a second precipitate, and (i') The second mixture is filtered to retain the second precipitate. The process according to claim 16, further comprising:

25. The second precipitate is a) Compound of formula (I) and b) Compounds of formula (II), compound (III), and compound (IV): 【Chemistry 15】 Or an impurity selected from the group consisting of combinations thereof, which is present in the composition at an area ratio of 2% or less by high-performance liquid chromatography (HPLC) and The process according to claim 23 or 24, wherein the composition comprises the composition.

26. The process according to any one of claims 22 to 24, wherein the first solvent is selected from 2-MeTHF and acetone.

27. ​​The process according to claim 26, wherein the first solvent is 2-MeTHF.

28. The process according to claim 26, wherein the first solvent is acetone.

29. The process according to claim 23 or 24, wherein the second solvent is n-heptane.

30. The process according to claim 23 or 24, further comprising the step of drying the second precipitate.

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