Therapeutic compounds, formulations and uses thereof

Abstract

The present disclosure relates, in part, to compositions comprising a compound of formula (I), processes for producing the compositions, and uses of the compositions, wherein the compositions are substantially free of impurities. # imgabs0 #

Description

[0001] Cross-references

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 369,055, filed on July 21, 2022, which is incorporated herein by reference in its entirety.

[0003] Overview

[0004] In certain embodiments, disclosed herein are compositions comprising a compound of formula (I), wherein the composition is substantially free of impurities; processes for producing the compositions; and uses of the compositions, such as in treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer, fibrosis, and inflammatory diseases or disorders).

[0005] In certain embodiments, disclosed herein is a composition comprising a compound of formula (I):

[0006]

[0007] wherein the composition is substantially free of impurities.

[0008] In certain embodiments, disclosed herein is a composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, wherein the composition is substantially free of impurities.

[0009] In certain embodiments, disclosed herein is a composition comprising a compound of formula (I), wherein the composition comprises no more than about 2% of a compound of formula (II).

[0010] In certain embodiments, disclosed herein is a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein the composition comprises no more than about 2% of the compound of formula (II).

[0011] In certain embodiments, disclosed herein is a composition comprising a compound of formula (I), wherein the composition comprises no more than about 0.05% of a compound of formula (III).

[0012] In certain embodiments, disclosed herein is a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein the composition comprises no more than about 0.05% of the compound of formula (III).

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

[0015] In certain embodiments, provided herein is a method of 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.

[0016] 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.

[0017] In certain embodiments, provided herein is a method of treating diabetic neuropathy in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0018] In certain embodiments, provided herein is a method of treating familial amyloid polyneuropathy in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0019] In certain embodiments, provided herein is a method of treating cachexia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0020] In certain embodiments, provided herein is a method of treating anaphylaxis in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0021] In certain embodiments, provided herein is 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.

[0022] In certain embodiments, provided herein is the use of a composition disclosed herein for treating cancer in an individual in need thereof.

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

[0024] 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.

[0025] In certain embodiments, provided herein is a use of a composition disclosed herein for treating chemotherapy-induced peripheral neuropathy in an individual in need thereof.

[0026] In certain embodiments, provided herein is a use of a composition disclosed herein for treating diabetic neuropathy in an individual in need thereof.

[0027] In certain embodiments, provided herein is a use of a composition disclosed herein for treating familial amyloid polyneuropathy in an individual in need thereof.

[0028] In certain embodiments, provided herein is the use of a composition disclosed herein for treating cachexia in an individual in need thereof.

[0029] In certain embodiments, provided herein is the use of a composition disclosed herein for treating an allergic reaction in an individual in need thereof.

[0030] In certain embodiments, provided herein is the use of a composition disclosed herein for treating an allergic reaction in an individual in need thereof.

[0031] 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.

[0032] In certain embodiments, disclosed herein is a method of evaluating the purity of a composition comprising a compound of formula (I), the method comprising determining in the composition 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).

[0033] In certain embodiments, disclosed herein is a process for preparing a compound of Formula (I) substantially free of impurities.

[0034] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 An exemplary reaction of compound 7 in DMSO-d6 is shown. 1 H-NMR spectrum.

[0037] Figure 2 An exemplary reaction of compound 7 in DMSO-d6 is shown. 13 C-NMR spectroscopy.

[0038] Details

[0039] In certain embodiments, the present disclosure provides compositions comprising a compound of formula (I),

[0040]

[0041] wherein the composition is substantially free of impurities; a process for producing the composition; and a method for treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer, fibrosis, inflammatory diseases or disorders) by administering the composition.

[0042] definition

[0043] As used herein in the specification, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising", the word "a" or "an" may mean one or more. As used herein, "another" may mean at least a second or more. Still further, the terms "having", "including", "containing" and "comprising" are interchangeable, and those skilled in the art recognize that these terms are open terms. Some embodiments of the present disclosure may be composed of or substantially composed of one or more elements, method steps and / or methods of the present disclosure. It is contemplated that any method, compound or composition described herein may be implemented relative to any other method, compound or composition described herein.

[0044] "About" and "approximately" shall generally mean an acceptable degree of error for the amount measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0045] As used herein, "pharmaceutically acceptable salts" refer to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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 acid addition salts are salts of amino groups formed with inorganic acids or with organic acids or formed by using other methods used in the art, such as ion exchange, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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.

[0046] As used herein, "pharmaceutically acceptable excipient" refers to any substance other than the active pharmaceutical ingredient in a pharmaceutical formulation. Exemplary pharmaceutical excipients include those that aid in the manufacturing process; protect, support, or enhance stability; increase bioavailability; or increase patient acceptability. They may also 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.

[0047] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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 active supervision by medical personnel.

[0048] Disease, disorder, and condition are used interchangeably herein.

[0049] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions that occur in a subject suffering from a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition or to reverse or slow the progression of the disease, disorder, or condition (also referred to as "therapeutic treatment").

[0050] Typically, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present disclosure may 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., to treat, prevent, and / or improve cancer in a subject, or to inhibit protein-protein interactions mediated by SH2 domains in a subject, at a reasonable benefit / 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 means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may encompass an amount that improves the entire therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. 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" may encompass an amount that improves overall prevention or an amount that enhances the prophylactic efficacy of another prophylactic agent. "Prophylactic treatment" contemplates actions that occur before a subject begins to suffer from a particular disease, disorder, or condition.

[0051] As used herein, the term "impurity" refers to a substance in a composition that is not a desired product (e.g., a compound of formula (I)) or an expected pharmaceutically acceptable carrier or excipient. Exemplary impurities include, but are not limited to, synthetic impurities, intermediate impurities, isomers, oxidation products, hydrolysis products, dimerization products, and decomposition products of a compound of formula (I) and / or reactants or residual solvents used in the process for preparing a compound of formula (I). Exemplary structures of such impurities (compounds of formula (II), compounds of formula (III), compounds of formula (IV)) are shown below:

[0052]

[0053] The term "substantially free" with respect to compositions described herein refers to compositions comprising at least a specific weight percentage free of a compound of formula (I) of one or more impurities. The specific weight percentage of impurities 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%, between 0% and 2%, between 0% and 5%, between 0% and 10%, or between 0% and 20%.

[0054] As used herein, ambient temperature conditions refer to temperatures between about 15°C to about 30°C or between about 20°C to about 30°C, such as between about 20°C to about 25°C.

[0055] Composition

[0056] Certain impurities may be incompatible with other substances (such as carriers) in the composition when formulated into a pharmaceutical composition comprising an active pharmaceutical ingredient and a pharmaceutically acceptable carrier; reduce the shelf life of the composition; cause difficulties during the preparation and use of the composition; cause physical and chemical instability of the composition; reduce the therapeutic effect of the composition; show adverse biological effects; or change the smell, color or taste of the composition. In certain embodiments, the composition comprising a compound of formula (I) as described herein is synthesized and processed in a manner that produces a composition that is substantially free of impurities. In addition, in certain embodiments, the composition comprising a compound of formula (I) as described herein is synthesized and processed to produce a sufficient amount of the compound of formula (I) (e.g., manufacturing scale, e.g., each batch produces a compound of formula (I) greater than or equal to 1 kg), while producing a composition that is substantially free of impurities.

[0057] In some embodiments, disclosed herein are compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0058]

[0059] wherein the composition is substantially free of impurities.

[0060] In some embodiments, the impurity is a synthetic impurity, an intermediate impurity, an oxidation product, a hydrolysis product of an impurity, a dimerization product or a decomposition product of a compound of formula (I). In some embodiments, the impurity is a reactant or a residual solvent in a process for preparing a compound of formula (I).

[0061] In some embodiments, the impurity is a compound of formula (II):

[0062]

[0063] In some embodiments, the impurity is a compound of formula (III):

[0064]

[0065] In some embodiments, the impurity is a compound of formula (IV):

[0066]

[0067] In some embodiments, the impurity is present in the composition at no more than about 2% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 1% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.5% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.4% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.3% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.2% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.1% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.09% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.08% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.07% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.06% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.05% area percentage according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.04% area percent according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.03% area percent according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.02% area percent according to HPLC. In some embodiments, the impurity is present in the composition at no more than about 0.01% area percent according to HPLC. In some embodiments, the amount of impurity in the composition cannot be detected by HPLC.

[0068] In some embodiments, the composition comprises one or more impurities not exceeding about 2% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 1% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.5% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.4% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.3% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.2% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.1% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.09% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.08% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.07% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities not exceeding about 0.06% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities that do not exceed about 0.05% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities that do not exceed about 0.04% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities that do not exceed about 0.03% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities that do not exceed about 0.02% area percentage according to HPLC. In some embodiments, the composition comprises one or more impurities that do not exceed about 0.01% area percentage according to HPLC.

[0069] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.5% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.4% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.3% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.2% area percentage according to HPLC after the composition is stored 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 comprises no more than about 0.1% area percent of one or more impurities according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 6 months.

[0070] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.5% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.4% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.3% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.2% area percentage according to HPLC after the composition is stored 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 no more than about 0.1% area percent of one or more impurities according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0071] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.5% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.4% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.3% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.2% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percent of one or more impurities according to HPLC after storing the composition at about 40°C and about 75% relative humidity for about 2 months.

[0072] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.5% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.4% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.3% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.2% area percentage according to HPLC after the composition is stored 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 comprises no more than about 0.1% area percent of one or more impurities according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0073] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (II) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0074] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1 area percent of a compound of Formula (II) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 2 months.

[0075] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored 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 comprises no more than about 0.1% area percent of a compound of Formula (II) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0076] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months.

[0077] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months.

[0078] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month.

[0079] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 3 months.

[0080] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 2 months. In some embodiments, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 2 months.

[0081] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 comprises no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 40° C. and about 75% relative humidity for about 1 month.

[0082] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.2% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months.

[0083] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.2% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months.

[0084] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.2% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months.

[0085] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.2% area percentage according to HPLC after the composition is stored at about 40°C and about 75% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months.

[0086] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.2% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months.

[0087] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.3% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.2% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof contains one or more impurities of no more than about 0.1% area percentage according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month.

[0088] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months.

[0089] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months.

[0090] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months.

[0091] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months.

[0092] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months.

[0093] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (II) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month.

[0094] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months.

[0095] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months.

[0096] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months.

[0097] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months.

[0098] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months.

[0099] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.08% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.05% area percentage of a compound of formula (III) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month.

[0100] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 24 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25° C. and about 60% relative humidity for about 24 months.

[0101] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 12 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25°C and about 60% relative humidity for about 12 months.

[0102] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 6 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25°C and about 60% relative humidity for about 6 months.

[0103] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 3 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25°C and about 60% relative humidity for about 3 months.

[0104] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 2 months. In some embodiments, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25°C and about 60% relative humidity for about 2 months.

[0105] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.5% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.4% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.3% area percentage of a compound of formula (IV) according to HPLC after the composition is stored at about 25°C and about 60% relative humidity for about 1 month. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% area percentage of a compound of formula (IV) according to HPLC after the composition is stored 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 no more than about 0.1% area percent of a compound of Formula (IV) according to HPLC after storing the composition at about 25°C and about 60% relative humidity for about 1 month.

[0106] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 2% of a compound of formula (II) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1.5% of a compound of formula (II) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1% of a compound of formula (II) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.5% of a compound of formula (II) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.1% of a compound of formula (II) by weight.

[0107] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 2% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1.5% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.5% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.1% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.09% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.08% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.07% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.06% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.05% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.04% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.03% of a compound of formula (III) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.02% by weight of a compound of formula (III). In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.01% by weight of a compound of formula (III).

[0108] In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 2% of a compound of formula (IV) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1.5% of a compound of formula (IV) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 1% of a compound of formula (IV) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.5% of a compound of formula (IV) by weight. In some embodiments, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises no more than 0.1% of a compound of formula (IV) by weight.

[0109] Preparation method

[0110] The compositions described herein are prepared using any of the methods described herein. For example, a composition comprising a compound of formula (I) substantially free of impurities:

[0111]

[0112] Prepared by a process comprising:

[0113] (a) Compound 2:

[0114]

[0115] Contact with Compound 1:

[0116]

[0117] To produce compound 3:

[0118]

[0119] (b) contacting compound 3 with an oxidizing agent to produce compound 4:

[0120]

[0121] (c) contacting compound 4 with compound 5 in the presence of a coupling agent:

[0122]

[0123] To produce a compound of formula (I);

[0124] (d) contacting the compound of formula (I) of step (c) with alcohol, water or a combination thereof to form a mixture; and

[0125] (e) filtering the mixture from step (d) to isolate a precipitate, wherein the precipitate is a composition comprising a compound of Formula (I) substantially free of impurities.

[0126] In some embodiments, the oxidizing agent is a periodate. In some embodiments, the oxidizing agent is sodium periodate or potassium periodate. In some embodiments, the coupling agent is boron trifluoride etherate.

[0127] In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, propanol and hexanol or a mixture 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.

[0128] In some embodiments, in step (d), the compound of formula (I) of step (c) is contacted with a combination of an alcohol and water to form a mixture. In some embodiments, the alcohol is isopropanol.

[0129] In some embodiments, the process further comprises, after step (e):

[0130] (f) dissolving the precipitate in a first solvent to form a mixture, and washing the mixture with a washing solution selected from the group consisting of brine, water, and combinations thereof; and

[0131] (g) separating the mixture of step (f) from the washing solution to obtain a separated mixture; and optionally

[0132] (h) concentrating the separated mixture of step (g) to form a concentrated mixture.

[0133] 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.

[0134] In some embodiments, the process further comprises, after step (h):

[0135] (i) contacting the concentrated mixture with a first solvent and adding charcoal to form a precipitate / charcoal mixture;

[0136] (j) filtering the precipitate / charcoal mixture to form a filtrate;

[0137] (k) adding a second solvent to the filtrate to form a second mixture comprising a second precipitate; and

[0138] (l) filtering the second mixture to retain the second precipitate.

[0139] In some embodiments, the process further comprises drying the second precipitate after step (1).

[0140] 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.

[0141] In some embodiments, the second solvent is pentane, hexane or heptane or a mixture thereof. In some embodiments, the second solvent is n-heptane.

[0142] In some embodiments, the process further comprises, after step (e):

[0143] (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;

[0144] (g') filtering the compound of formula (I) / charcoal mixture to separate a filtrate comprising the compound of formula (I) (eg, wherein the filtering separates the charcoal from the filtrate comprising the compound of formula (I));

[0145] (h') adding a second solvent to the filtrate of step (g') to form a second mixture comprising a second precipitate, the second precipitate comprising a compound of formula (I); and

[0146] (i') filtering the second mixture of step (h') to isolate a second precipitate comprising the compound of formula (I).

[0147] In some embodiments, the process further comprises, after step (i'), drying the second precipitate.

[0148] 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.

[0149] In some embodiments, the second solvent is pentane, hexane or heptane or a mixture thereof. In some embodiments, the second solvent is n-heptane.

[0150] In some embodiments, the impurity is an oxidation product 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.

[0151] In some embodiments, the method produces greater than or equal to 1kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 2kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 3kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 4kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 5kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 10kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 15kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 20kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 30kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 40kg of a compound of formula (I). In some embodiments, the method produces greater than or equal to 50kg of a compound of formula (I).

[0152] Also disclosed herein is a method of evaluating a composition comprising a compound of formula (I):

[0153]

[0154] The method comprises determining in the composition the presence of a compound selected from the group consisting of:

[0155]

[0156] In some embodiments, determination includes analysis using HPLC (high performance liquid chromatography). In some embodiments, determination includes analysis using MS (mass spectrometry). In some embodiments, determination includes analysis using LC-MS (liquid chromatography-mass spectrometry). In some embodiments, determination includes analysis using NMR (nuclear magnetic resonance). In some embodiments, determination includes analysis using IR (infrared spectroscopy). In some embodiments, determination includes analysis using UV (ultraviolet-visible spectroscopy). In some embodiments, determination includes analysis using a combination of HPLC, MS, LC-MS, NMR, IR or UV.

[0157] In some embodiments, the method of evaluating a composition comprising a compound of Formula (I) further comprises determining the amount of a compound selected from the group consisting of:

[0158]

[0159] Pharmaceutical compositions, administration and dosage

[0160] Compositions disclosed herein may also include pharmaceutically acceptable carriers, including but not limited to inert solid diluents and fillers, diluents (including sterile aqueous solutions and a variety of organic solvents), penetration enhancers, solubilizers and adjuvants. Pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in any suitable manner (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker and CT Rhodes, ed.).

[0161] The pharmaceutical composition can be administered in single or multiple doses by any accepted mode of administration for agents with similar utilities, e.g., as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent, or an arterially inserted cylindrical polymer.

[0162] A mode of administration is parenteral, particularly by injection. The form of administration by injection of the composition that can be incorporated into the present disclosure includes aqueous or oily suspensions or emulsions with 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 routinely used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. For example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion and by using a surfactant, suitable fluidity can be maintained. The effect of preventing microorganisms can be achieved by a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.

[0163] Sterile injectable solutions are prepared by incorporating the desired amount of the composition according to the present disclosure into an appropriate solvent, followed by filtration sterilization, the solvent having a variety of other ingredients as listed above as required. Typically, dispersions are prepared by incorporating a variety of sterilized active ingredients into a sterile vehicle comprising a basic dispersion medium and other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying techniques and freeze drying techniques, which produce powders thereof from a previously sterile filtered solution of the active ingredient plus any additional desired ingredients.

[0164] Oral administration is another approach for administering the composition according to the present disclosure. Administration can be via capsules or enteric coated tablets, etc. In the preparation of pharmaceutical compositions comprising compounds described herein, the active ingredient is usually diluted and / or encapsulated in such a carrier by an excipient: the carrier can be in the form of a capsule, a pouch, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid material, a semisolid material or a liquid material (as above) that serves as a vehicle, a carrier or a medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, pouches, cachets (caches), elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0165] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrups and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners and flavoring agents.

[0166] The compositions disclosed herein can be formulated by employing procedures known in the art so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

[0167] In some embodiments, the composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material combined with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule) calculated to produce a desired therapeutic effect. The composition is usually administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably contains from 0.1 mg to 1000 mg of the compound described herein. However, it should be understood that the amount of the compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0168] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms such as tablets, pills and capsules.

[0169] The tablet or pill of the present disclosure can be coated or otherwise compounded to provide a dosage form with an extended effect advantage, or to protect against the acidic conditions of the stomach. For example, tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form encapsulated in the former. Two components can be separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to pass completely through entering the duodenum or delaying release. Various materials can be used for such enteric layers or coatings, and such materials include a mixture of multiple polymeric acids and polymeric acids and materials such as shellac, cetyl alcohol and cellulose acetate.

[0170] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid compositions or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. Preferably, the composition in a pharmaceutically acceptable solvent can be atomized by using an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be attached to a face mask tent or an intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered from a device that delivers the preparation in an appropriate manner, preferably orally or nasally.

[0171] In some embodiments, the composition comprising a 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.

[0172] The dosage can vary depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dosage can be selected by an individual physician in view of the patient's condition. (See, for example, Fingl et al., 1975, "The Pharmacological Basis of Therapeutics"). A lower or higher dosage than the dosage 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, excretion rate, drug combination, severity and progression of the disease, condition or symptom, the subject's tendency to the disease, condition or symptom, and the judgment of the treating physician. The course of therapy may include one or more separate administrations of the compound as described herein.

[0173] How to use

[0174] Also provided herein, in certain embodiments, are methods of using a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a therapeutic or other method described herein, wherein the composition is substantially free of impurities.

[0175] In some embodiments, the method comprises administering a compound of formula (I) (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, the compound of formula (I) (e.g., as formulated herein, e.g., as an oral dosage form) is used in a method for treating, preventing, or reducing the risk or severity of a disease or disorder mediated by STAT3 or a disease or disorder that is otherwise treatable with a STAT3 inhibitor. For example, the compositions described herein can be used to treat, prevent, or reduce the risk or severity of certain diseases or disorders characterized by excessive STAT3 protein expression. In specific embodiments, methods for treating, preventing, or reducing the risk or severity of cancer are provided herein. In other specific embodiments, methods for treating, preventing, or reducing the risk or severity of fibrosis are provided herein. In still other specific embodiments, methods for treating, preventing, or reducing the risk or severity of inflammatory diseases / disorders are provided herein.

[0176] Signal transducer and activator of transcription 3 (STAT3) is the core of regulating anti-tumor immune response.STAT3 is widely overactivated in both cancer cells and non-cancerous cells in the tumor ecosystem, and plays an important role in suppressing the expression of key immune activation regulatory factors and promoting the generation of immunosuppressive factors.The method provided herein is expected to be useful for treating cancer, including, for example, solid tumors, soft tissue tumors and metastatic tumors thereof.

[0177] In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of cancer in an individual in need thereof is provided, the method comprising administering any composition described herein to an 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 (gastric cancer), skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach 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 (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 according to 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.

[0178] In some embodiments, provided herein is a method of treating cancer 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 cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, bone cancer, spleen cancer, gallbladder cancer, stomach cancer, anal cancer, post-transplant lymphoproliferative disease, restenosis, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain cancer, 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.

[0179] In addition, STAT3 is important for Th17 lymphocyte development and cytokine production, and its activation is associated with the development of airway inflammation. After activation, STAT3 is recruited to the cytokine-activated receptor complex and becomes phosphorylated at Tyr (Y) 705. Phospho-tyrosinated (p) STAT3 homodimerizes through mutual SH2-pY705 interactions, shifts to the nucleus, and binds to the promoter to transcriptionally activate genes that drive Th17 differentiation and the production of various cytokines. STAT3 activation is also involved in the production of Th2 cytokines, making it an attractive target for the treatment of asthma. In addition, several genes have been considered as risk factors for inflammatory bowel disease (IBD) in genome-wide association studies (GWAS), including ATG16L, NOD2 / CARD15, IBD5, CTLA4, TNFSF15, JAK2, STAT3, IL23R and ORMDL3, which are related to antimicrobial peptides, innate and adaptive immune cell functions, Th17 cells, regulatory T cells (Tregs) and cytokines (tumor necrosis factor, interleukin 17, interleukin 23, interleukin 12, interleukin 22 and IL-6). Many of these cytokines are used as ligands for the cell surface receptors that activate STAT3. STAT3 in three cell lineages (myeloid cells, intestinal epithelial cells and T cells) causes colitis in mice and humans. Therefore, targeting STAT3 represents an effective means for treating, preventing inflammatory diseases / disorders or reducing the risk or severity of inflammatory diseases / disorders.

[0180] In certain embodiments herein, there is provided a method for treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder in an individual with corresponding needs, the method comprising administering any composition described herein to an individual. In some embodiments, the inflammatory disease / disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, allergic reaction, cancer cachexia, chronic kidney disease cachexia, non-alcoholic fatty liver disease (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, allergic reaction, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic fatty liver disease (NASH). In some embodiments, allergic reactions include anaphylactic shock.

[0181] In some embodiments, provided herein is 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.

[0182] In some embodiments, provided herein is a method of 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, scleritis, multiple sclerosis, pancreatitis, or asthma.

[0183] Fibrosis is a pathological process that involves excessive extracellular matrix accumulation in tissues, leading to tissue damage and organ dysfunction, which can progress to organ failure and death. In systemic sclerosis (a kind of idiopathic fibrosis), it is assumed that the triggering factor is an autoimmune response, which leads to the production of tissue damage, growth factors, proinflammatory and profibrotic cytokines and the accumulation of myofibroblasts. Two potential sources of myofibroblasts are the differentiation of local fibroblasts and the process of epithelial to mesenchymal transition (EMT). IL-6 is a proinflammatory and profibrotic cytokine that is increasingly considered to be an important mediator of fibrosis, and the proinflammatory and profibrotic cytokines contribute to the accumulation of myofibroblasts. After engaging its receptor, IL-6 is conducted by STAT3 signaling. Therefore, STAT3 represents a potential important protein for targeted therapy of fibrosis.

[0184] In certain embodiments herein, a method of treating, preventing, or reducing the risk or severity of fibrosis in an individual in need thereof is provided, the method comprising administering to the individual any composition described herein. In certain embodiments, fibrosis is associated with a disorder or disease such as skin fibrosis (or dermal fibrosis), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal fibrosis, renal fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or limited 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, fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, myelofibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, or pulmonary fibrosis.

[0185] In some embodiments, provided herein is a method of treating fibrosis 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, fibrosis is associated with pulmonary fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, renal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In some embodiments, fibrosis is associated with pulmonary fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

[0186] In certain embodiments, fibrosis is associated with 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, primary biliary cirrhosis, fibrosis following viral infection involving the heart, liver, or lungs, and / or idiopathic retroperitoneal fibrosis.

[0187] 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, inhibition of myostatin reduced circulating levels of IL-6 and TNFα, suggesting a link 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 involved in the loss of muscle mass.

[0188] In certain embodiments herein, a method 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 is provided, the method comprising administering to the individual any composition described herein. Muscle weakness and / or muscle wasting and / or cachexia may have an unknown cause, or it may be associated with an underlying condition. The underlying condition may be a catabolic condition. In some embodiments, the underlying medical condition associated with cachexia is at least renal disease or renal 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, infectious diseases, chronic pancreatitis, autoimmune disorders, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease disease, sepsis, burns, trauma, fever, long bone fractures, hyperthyroidism, long-term steroid therapy, surgery, bone marrow transplantation, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, paraneoplastic syndromes, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dermatomyositis, rheumatic diseases, autoimmune diseases, collagen vascular diseases, visceral leishmaniasis, prolonged bed rest, and / or addiction to drugs such as amphetamines, opioids, or barbiturates.

[0189] In some embodiments, provided herein is a method of treating cachexia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0190] In addition, STAT3 signaling has been implicated in gap junction intercellular communication, IL-6 and IL-11-induced vascular leakage, downregulation of VE-cadherin with STAT3 phosphorylation, and STAT3 / mirl7-92 / E2F1-dependent regulation of β-catenin nuclear translocation and transcriptional activity. Therefore, STAT3 inhibition may be useful in reducing vascular permeability in the context of allergic reactions.

[0191] In some embodiments, provided herein is a method of treating an allergic reaction in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0192] In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of an allergic reaction in an individual in need thereof is provided, the method comprising administering to an individual any composition described herein. 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, beans, shellfish, nuts, eggs, fish, soybeans, and wheat), an environmental allergen or a seasonal allergen (such as pollen or mold), a venom allergen (such as from wasps, bees, ants, hornets, yellow jackets, or asps), a drug allergen (such as an anesthetic, beta-lactam antibiotic, aspirin, nonsteroidal anti-inflammatory drugs, chemotherapy, vaccines, protamine, or herbal preparations) or latex. In some embodiments, the allergic reaction is anaphylactic reaction, anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenopteran allergy, bronchoconstriction, asthma, or eczema.

[0193] STAT3 also plays an important role in viral infection and pathogenesis. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of a viral infection in an individual in need thereof is provided, the method comprising administering any composition 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.

[0194] In addition, reactive astrocytes in neurodegenerative diseases including Alzheimer's disease are related to STAT3 phosphorylation. The pathophysiological effects of astrocytes in a reactive state are considered to be of great significance in the pathogenesis of neurodegenerative diseases. In certain embodiments herein, treatment, prevention of neurodegenerative diseases of individuals with corresponding needs or methods for reducing the risk or severity of the neurodegenerative diseases are provided, the method comprising administering any composition described herein to the individual. In some embodiments, neurodegenerative diseases are peripheral neuropathy, diabetic neuropathy or chemobrain induced by chemotherapy. In certain embodiments herein, treatment, prevention of pain of individuals with corresponding needs or methods for reducing the risk or severity of the pain are provided, the method comprising administering any composition described herein to the individual. In some embodiments, pain is neuropathic pain. In certain embodiments herein, methods are provided for treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagasic cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

[0195] In some embodiments, provided herein is a method for treating a neurodegenerative 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, provided herein is a method for 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. In some embodiments, provided herein is a method for treating diabetic neuropathy 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, provided herein is a method for treating familial amyloid polyneuropathy in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition disclosed herein.

[0196] STAT3 is involved in cytokine-induced insulin resistance and nutrient-induced insulin resistance, and excessive STAT3 signaling is involved in the development of insulin resistance, such as skeletal muscle insulin resistance in type 2 diabetes. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of insulin resistance in an individual in need thereof is provided, the method comprising administering any composition described herein to the individual. In some embodiments, insulin resistance is the result of an underlying condition. In some embodiments, insulin resistance is associated with the muscles of the individual being treated. In some embodiments, insulin resistance is caused by any cause of the individual, such as elevated free fatty acids in the blood, obesity, overweight, having visceral fat, having high fructose intake, having inflammation, inactivity, dysbiosis of the intestinal microbiota, and / or genetic susceptibility. In certain embodiments, any of the methods provided herein is a method of treating, preventing, or reducing the risk or severity of a medical condition associated with insulin resistance or at least in part a complication of insulin resistance; such as, for example, severe hyperglycemia, severe hypoglycemia; heart attack; stroke; kidney disease (including chronic, such as chronic kidney disease (CKD)); eye problems; cancer; non-alcoholic fatty liver disease (NAFLD); polycystic ovary syndrome (PCOS); metabolic syndrome; diabetes; or Alzheimer's disease. In certain embodiments, insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes. Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Its symptoms include high blood triglycerides, blood pressure, abdominal fat and blood sugar, and low HDL (good) cholesterol levels.

[0197] In some embodiments, provided herein is 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.

[0198] In some embodiments, the method includes administering a therapeutically effective amount of a composition disclosed herein to an individual. In certain embodiments, the method includes administering to an individual a compound of formula (I) of at least 1 mg / kg / day. In certain embodiments, the method includes administering to an individual a compound of formula (I) of at least 10 mg / kg / day. In certain embodiments, the method includes administering to an individual a compound of formula (I) of at least 20 mg / kg / day. In certain embodiments, the method includes administering to an individual a compound of formula (I) of at least 25 mg / kg / day. Example

[0199] Exemplary HPLC conditions: diluent is 0.1% trifluoroacetic acid (TFA) in acetonitrile, mobile phase A is 0.05% TFA in water and mobile phase B is 0.05% TFA in acetonitrile, column (Agilent, Eclipse XDB-C18, 3.0×100 mm, particle size 1.8 μm), flow rate (0.425 mL / min), and detector (280 nm diode array).

[0200] Example 1. Synthesis of TTI-101

[0201]

[0202] Scheme 1. Process for preparing TTI-101 (compound of formula (I))

[0203] Method 1

[0204] A mixture of 4-aminonaphthalene-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 about 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 provide compound 3 (466 g, 98.5% yield).

[0205] Dichloromethane (DCM) (7L) and silica gel (830g) are added to the solution of sodium periodate (105g) in water (466g) and the mixture is stirred.Compound 3 (451g) in DCM (1.4L) is added to the mixture and stirring continues for 6 hours.Then, sodium sulfate (707g) is added to the mixture and stirring continues for 2 hours.The mixture is filtered and rinsed with DCM.2-naphthol (200g) and boron trifluoride diethyl etherate (boron trifluoride diethyl etherate) (8mL, 0.06mol) are added to the mixture, and stirring continues for about 0.5 hour at 38 ° C. Additional boron trifluoride diethyl ether (8mL, 0.06mol) is added to the mixture and stirred at 38 ° C for 2.5 hours.The reaction mixture is cooled to room temperature, filtered and dried under reduced pressure, to provide TTI-101 (616g, 95.3% yield, according to 99.5% purity of HPLC). The collected solid was dissolved in acetone (4.5 L). Activated carbon (123 g) was added to the solution and stirred for about 2 hours. Filter. Then, n-heptane (8 L) was added to the combined filtrate, stirred, and allowed to stand overnight to provide a slurry. The slurry was filtered and the solid was dried under pressure for 18 hours to provide TTI-101 (556 g, 86.0% overall yield, 99.8214% purity according to HPLC). HPLC analysis also showed that compound 6 was 0.1111% AUC and compound 7 was about 0.02% AUC:

[0206]

[0207] Method 1-a: TTI-101 (10.03 g) obtained by method 1 described above was combined with acetone (40 mL) under stirring under nitrogen. More acetone (33 mL) was added to the mixture while heating to 53 ° C and stirring to dissolve the solid by a hood. Heptane (55 mL) was added in batches with stirring, and the resulting slurry was cooled to 22 ° C and then further cooled at 4 ° C-5 ° C. The slurry was filtered through a funnel under reduced pressure with a cooled solvent (1: 1 acetone to 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 separated solid was determined by HPLC (80.8% recovery) to be 99.8445% AUC, and compound 6 was 0.1047% AUC.

[0208] Method 1-b: TTI-101 (9.82 g) obtained by Method 1 described above was combined with 1:1 acetone and heptane (100 mL) under stirring at ambient temperature under nitrogen and then cooled in an ice / water bath. The resulting slurry was filtered through a funnel under reduced pressure with the cooled 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 was determined by HPLC (82.5% recovery) to be 99.8404% AUC, and compound 6 was 0.0982% AUC.

[0209] Method 2

[0210] 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. Prior to the recrystallization process and / or slurry process in Table 1, this batch also contained Compound 6.

[0211] Table 1 describes exemplary recrystallization and / or slurrying of TTI-101 from a batch obtained according to Method 2.

[0212] Table 1.

[0213]

[0214]

[0215]

[0216]

[0217] Method 3

[0218] A mixture of 4-aminonaphthalene-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 provide compound 3 (7.79 kg, 92.7% yield).

[0219] A solution of sodium periodate (1.9kg) in water (34kg) was added to a mixture of compound 3 (7.0kg) in DCM (139kg). The resulting mixture was stirred at 20°C for 1 hour and kept 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 and diluted with DCM (70L), then distilled to a final volume of 70L. A solution of 2-naphthol (3.4kg) and boron trifluoride dibutyl ether (40.19g) in DCM (10L) was added to the mixture and stirred for 6.5 hours. The reaction mixture was quenched with 70% wet IPA (7L). The resulting solid was collected, dissolved in 2-MeTHF (105L) and washed with 10% brine (2×35L) and water (1×35L). The mixture was concentrated and loaded with acetone. The resulting mixture was loaded onto activated carbon and stirred for 12 hours. The mixture was stirred for 12 hours. The mixture was stirred for 2 hours at 45 °C and then cooled to 25 °C and stirred for 12 hours. The resulting solid was filtered, washed with a mixture of acetone / n-heptane, then washed with n-heptane, and then dried to provide TTI-101 (6.46 kg, 64.6% yield, 99.95% purity). The formation of compound 7 was not detected.

[0220] Another batch of TTI-101 was prepared according to Method 3 above to produce 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%, and the AUC of Compound 6 was 0.13%.

[0221] Another batch of TTI-101 was prepared according to Method 3 above to produce 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%, and the AUC of Compound 6 was 0.05%.

[0222] Another batch of TTI-101 was prepared according to Method 3 above to produce 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%, and the AUC of Compound 6 was 0.09%.

[0223] Method 4

[0224] The batch (6.4 kg) of TTI-101 from method 3 was dissolved in 2-MeTHF, warmed to 50°C, then cooled to 35°C and transferred to a reactor containing n-heptane over 4 hours through an in-line filter (0.45 micron). The resulting slurry was adjusted to 25°C ± 5°C and stirred at 25°C ± 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 deblocked to give TTI-101 (5.89 kg, 92.0% yield, 99.76% purity). The formation of compound 7 was not detected.

[0225] Method 5

[0226] A mixture of 4-aminonaphthalene-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 provide compound 3 (7.78 kg, 92.6% yield).

[0227] 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 stirred by Filter and wash with DCM. Separate the layers and wash the organic layer with brine twice. The mixture is vacuum distilled twice and diluted with DCM (70L), then distilled to a final volume of 70L. Add 2-naphthol (3.4kg) and a solution of boron trifluoride dibutyl ether (61.0g) in DCM (10L) to the mixture and stir for 6 hours. The reaction mixture is quenched with 70% wet IPA (7L). Collect the resulting solid, wash with DCM and dry. The solid is dissolved in 2-MeTHF (105L) and washed with 10% brine (2×35L) and water (1×35L). The resulting mixture is loaded onto activated carbon and stirred for 12 hours. The mixture is stirred for 12 hours. Filtered 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 provide TTI-101 (5.85 kg, 58.5% yield, 99.42% purity). The formation of compound 7 was not detected.

[0228] Example 2. Synthesis of Compound 7

[0229] Method A

[0230] TTI-101 (0.52 g) and boron trifluoride etherate (0.13 mL) were stirred at 38° C. in DCM (25 mL) under nitrogen 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 at 42° C. under reduced pressure. HPLC analysis showed a conversion of 1.93% to compound 7.

[0231] Method B

[0232] TTI-101 (0.51 g) and boron trifluoride etherate (0.33 mL) were stirred at 50°C in acetonitrile (25 mL) under nitrogen for about 4 days, and additional boron trifluoride etherate (0.20 mL) was added at the 30 hour point. The resulting slurry was cooled to ambient temperature, filtered under reduced pressure and washed with acetonitrile. The solid was dried at 50°C-55°C under reduced pressure. HPLC analysis showed that the AUC purity of compound 7 was 99.87%. The 1H-NMR and 13C-NMR of the product were respectively Figure 1 and Figure 2 Shown in.

[0233] Example 3. Accelerated stability and low temperature stability study of TTI-101

[0234] Batch A was prepared similarly using Method 3 as described in Example 1. Batch B was prepared according to Method 5 as described in Example 1.

[0235] Long-term stability of batch A

[0236] 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 tie, and then transferred to another LDPE bag and closed with a nylon tie. The closure was placed in an HDPE bottle and closed with a polyethylene-lined polypropylene cap. The samples were stored under the conditions determined above.

[0237] Long-term stability of batch B

[0238] 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 tie, and then transferred to another LDPE bag and closed with a nylon tie. The closure was placed in an HDPE bottle and closed with a polyethylene-lined polypropylene cap. The samples were stored under the conditions determined above.

[0239] The samples were analyzed using HPLC under the exemplary conditions identified above. The relative retention time (RRT) of compound 5 was about 0.83, compound 4 was about 1.05-1.06, compound 6 was about 1.15-1.17, and the compound of formula (IV) was about 0.99.

[0240] abbreviation:

[0241] NA Not applicable

[0242] NQ ≥ 0.02% and < 0.05%

[0243] Avg Average

[0244] Cmpd compound

[0245] - No peak

[0246] M month

[0247] RRT Relative Retention Time For batch A:

[0248] a) Storage conditions: 5℃:

[0249]

[0250]

[0251]

[0252] b)25℃ / 60%RH:

[0253]

[0254]

[0255]

[0256] c)40℃ / 75%RH:

[0257]

[0258]

[0259]

[0260] For batch B:

[0261] a) Storage conditions: 5℃:

[0262]

[0263]

[0264]

[0265]

[0266] b) Storage conditions: 25℃ / 60%RH:

[0267]

[0268]

[0269]

[0270]

[0271] Storage conditions: 40℃ / 75%RH:

[0272]

[0273]

[0274]

[0275]

[0276] Based on the stability testing of Batch A and Batch B above, Batch A showed excellent stability over 24 months.

[0277] 3-month stability data for Batch B, Batch C, Batch D and Batch E

[0278] Batch B, Batch C and Batch D were prepared according to Method 5, Method 4 and Method 3, respectively, as described in Example 1. Batch E was similarly prepared using Method 1 as described in Example 1.

[0279] Samples of TTI-101 (Batch B, Batch C, Batch D and Batch E) were stored at 40°C / 75% RH for 3 months. The batches were stored individually in low density polyethylene (LDPE) bags closed with nylon tie, and then transferred to another LDPE bag and closed with nylon tie. The closures were placed in high density polyethylene (HDPE) bottles and closed with polyethylene lined polypropylene caps. For batch B only, another sample was packaged in a screw cap amber glass bottle and closed with a cap. The samples were stored under the conditions determined above.

[0280] T=0month(0M)

[0281]

[0282] T=1 month(1M)

[0283]

[0284]

[0285] T=2 months(2M)

[0286]

[0287] T = 3 months (3M)

[0288]

[0289] Storage conditions: 40°C / 75% relative humidity (RH) Batch C:

[0290]

[0291]

[0292] Batch D:

[0293]

[0294] Batch B (LDPE storage):

[0295]

[0296] Batch B (Glass Storage):

[0297]

[0298] Batch E:

[0299]

Claims

1. A composition comprising a compound of formula (I): wherein the composition is substantially free of impurities.

2. The composition of claim 1, wherein the impurity is present in the composition at no more than about 2% area percent according to HPLC.

3. The composition of claim 1, wherein the impurity is present in the composition at no more than about 1% area percent according to HPLC.

4. The composition of claim 1, wherein the impurity is present in the composition at no more than about 0.5% area percent according to HPLC.

5. The composition of claim 1, wherein the impurity is present in the composition at no more than about 0.1% area percent according to HPLC.

6. The composition of claim 1, wherein the impurity is present in the composition at no more than about 0.05% area percent according to HPLC.

7. The composition of claim 1, wherein the amount of the impurity is not detectable by HPLC.

8. The composition according to any one of claims 1 to 7, wherein the impurity is an oxidation product of the compound of formula (I).

9. The composition according to claim 8, wherein the oxidation product is a compound of formula (II):

10. The composition of any one of claims 1-7, wherein the impurity is a synthetic impurity.

11. The composition according to claim 10, wherein the synthetic impurity is a compound of formula (III):

12. The composition according to any one of claims 1 to 7, wherein the impurity is a compound of formula (IV):

13. A composition comprising: (a) Compounds of formula (I): as well as (b) a pharmaceutically acceptable carrier, wherein the composition is substantially free of impurities.

14. The composition of claim 13, wherein the impurity is present in the composition at no more than about 2% area percent according to HPLC.

15. The composition of claim 13, wherein the impurity is present in the composition at no more than about 1% area percent according to HPLC.

16. The composition of claim 13, wherein the impurity is present in the composition at no more than about 0.5% area percent according to HPLC.

17. The composition of claim 13, wherein the impurity is present in the composition at no more than about 0.1% area percent according to HPLC.

18. The composition of claim 13, wherein the impurity is present in the composition at no more than about 0.05 area percent according to HPLC.

19. The composition of claim 13, wherein the amount of the impurity is not detectable by HPLC.

20. The composition of any one of claims 13-19, wherein the impurity is an oxidation product of the compound of formula (I).

21. The composition of claim 20, wherein the oxidation product is a compound of formula (II):

22. The composition of any one of claims 13-19, wherein the impurity is a synthetic impurity.

23. The composition of claim 22, wherein the synthetic impurity is a compound of formula (III):

24. The composition according to any one of claims 13-19, wherein the impurity is a compound of formula (IV):

25. A composition comprising a compound of formula (I): wherein the composition comprises no more than 2% of the compound of formula (II).

26. The composition of claim 25, wherein the composition comprises no more than 1% of the compound of formula (II).

27. The composition of claim 25, wherein the composition comprises no more than 0.2% of the compound of formula (II).

28. A composition comprising: (a) Compounds of formula (I): as well as (b) a pharmaceutically acceptable carrier, wherein the composition comprises no more than 2% of the compound of formula (II).

29. The composition of claim 28, wherein the composition comprises no more than 1% of the compound of formula (II).

30. The composition of claim 28, wherein the composition comprises no more than 0.2% of the compound of formula (II).

31. A composition comprising a compound of formula (I): wherein the composition comprises no more than 0.05% of the compound of formula (III).

32. The composition of claim 31, wherein the composition comprises no more than 0.01% of the compound of formula (III).

33. The composition of claim 31, wherein the amount of the compound of formula (III) is not detectable by HPLC.

34. A composition comprising: (a) Compounds of formula (I): as well as (b) a pharmaceutically acceptable carrier, wherein the composition comprises no more than 0.05% of the compound of formula (III).

35. The composition of claim 34, wherein the composition comprises no more than 0.01% of the compound of formula (III).

36. The composition of claim 34, wherein the amount of the compound of formula (III) is not detectable by HPLC.

37. The composition according to any one of claims 1-36, for use in treating cancer in an individual in need thereof.

38. The composition for use of claim 37, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, bone cancer, spleen cancer, gallbladder cancer, gastric cancer, anal cancer, post-transplant lymphoproliferative disease, restenosis, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain cancer, pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, or metastatic melanoma.

39. The composition for use according to claim 37, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia or pancreatic cancer.

40. The composition of any one of claims 1-36, for use in treating fibrosis in a subject in need thereof.

41. The composition for use of claim 40, wherein the fibrosis is associated with pulmonary fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, renal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

42. The composition for use according to claim 40, wherein the fibrosis is associated with pulmonary fibrosis, non-alcoholic fatty liver disease, steatohepatitis or systemic sclerosis.

43. A composition according to any one of claims 1-36 for use in treating an inflammatory disease or disorder in a subject in need thereof.

44. A composition according to any one of claims 1-36 for use in treating chemotherapy-induced peripheral neuropathy in a subject in need thereof.

45. A composition according to any one of claims 1-36 for use in treating diabetic neuropathy in a subject in need thereof.

46. ​​A composition according to any one of claims 1-36 for use in treating familial amyloid polyneuropathy in a subject in need thereof.

47. A composition according to any one of claims 1-36 for use in treating cachexia in a subject in need thereof.

48. A composition according to any one of claims 1-36 for use in treating an allergic reaction in a subject in need thereof.

49. The composition of any one of claims 1-36, for use in a method of treating non-alcoholic fatty liver disease or steatohepatitis in a subject in need thereof.

50. A method for evaluating the purity of a composition comprising a compound of formula (I): The method comprises determining the presence of a compound in the composition selected from the group consisting of:

51. The method of claim 50, wherein said determining comprises analyzing using HPLC.

52. The method of claim 50, further comprising determining the amount of a compound selected from the group consisting of:

53. A process for preparing a compound of formula (I) substantially free of impurities: The process comprises: (a) Compound 2: Contact with Compound 1: To produce compound 3: (b) contacting compound 3 with an oxidizing agent to produce compound 4: (c) contacting compound 4 with compound 5 in the presence of a coupling agent: To produce a crude compound of formula (I); (d) contacting the compound of formula (I) of step (c) with alcohol, water or a combination thereof to form a mixture; and (e) filtering the mixture of step (d) to separate a precipitate, wherein the precipitate is a compound of formula (I) substantially free of impurities.

54. A process according to claim 53, wherein the oxidizing agent is a periodate (e.g., sodium periodate or potassium periodate).

55. The process of claim 53, wherein the coupling agent is boron trifluoride etherate.

56. The process of claim 53, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, propanol, and hexanol.

57. The process of claim 56, wherein the alcohol is isopropanol.

58. The process of claim 53, wherein in step (d), the compound of formula (I) of step (c) is contacted with a combination of an alcohol and water to form the mixture.

59. The process of claim 53, further comprising, after step (e) of claim 53: (f) dissolving the precipitate in a first solvent to form a mixture, and washing the mixture with a washing solution selected from the group consisting of brine, water, and combinations thereof; and (g) separating the mixture of step (f) from the washing solution to obtain a separated mixture; and optionally (h) concentrating the separated mixture of step (g) to form a concentrated mixture.

60. The process of claim 59, further comprising, after step (h) of claim 59: (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 (1) filtering the second mixture to retain the second precipitate.

61. The process of claim 53, further comprising, after step (e) of claim 53: (f') dissolving the precipitate in a first solvent and adding charcoal to form a precipitate / charcoal mixture; (g') filtering the precipitate / charcoal mixture to form a filtrate; (h') adding a second solvent to the filtrate to form a second mixture comprising a second precipitate; and (i') filtering the second mixture to retain the second precipitate.

62. A process according to claim 60 or 61, wherein the second precipitate is a compound of formula (I) substantially free of impurities.

63. The process of any one of claims 59-62, wherein the first solvent is selected from 2-MeTHF and acetone.

64. The process of claim 59, wherein the first solvent is 2-MeTHF.

65. The process of claim 60 or 61, wherein the first solvent is acetone.

66. The process of any one of claims 59-65, wherein the second solvent is n-heptane.

67. The process of claim 60 or 61, further comprising drying the second precipitate.

68. The process of claim 62, wherein the impurity is an oxidation product of the compound of formula (I).

69. The process of claim 68, wherein the oxidation product is a compound of formula (II):

70. The process of claim 62, wherein the impurity is a synthetic impurity.

71. The process of claim 70, wherein the synthetic impurity is a compound of formula (III):

72. A composition comprising a compound of formula (I) prepared according to any one of claims 53-71.

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