Prodrug of a STAT3 inhibitor

Abstract

In certain embodiments, Formula I: 【Chemical 1】 Compounds of JPEG2025520456000046.jpg5339 or pharmaceutically acceptable salts or solvates thereof, compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and their use in the treatment of certain diseases or disorders (e.g., cancer, fibrosis, chronic inflammation) etc. are provided herein.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 366,437, filed Jun. 15, 2022, which is hereby incorporated by reference in its entirety.

Summary of the Invention

[0002] In certain embodiments, a composition is disclosed herein that comprises a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the compounds and compositions disclosed herein are effective to inhibit signal transducer and activator of transcription 3 (STAT3), and are thus useful in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders such as cancer, fibrosis, and inflammatory diseases or disorders.

[0003] In certain embodiments, Formula I:

[0004]

Chemical Formula

[0005] [Chemical formula] to form, provided that R 1 , R 2 , and R 3 are not simultaneously H, R A is H or C 1-4 alkyl, R B is amine, C 1-4 alkyl, or C 1-6 alkylene-N(H)(C 1-6 alkyl), C 1-6 alkylene-(5- to 8-membered heterocyclyl), C 1-6 alkylene-C(=O)OH, R C is C 1-4 alkyl or hydroxy, n is an integer of 0, 1, 2, or 3, and a compound or a pharmaceutically acceptable salt or solvate thereof is provided herein.

[0006] In certain embodiments, a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof described herein and a pharmaceutically acceptable carrier is provided herein.

[0007] In certain embodiments, provided herein are methods that include the use of a compound of formula (I), i.e., a STAT3 inhibitor (e.g., including administration), wherein the compound of formula (I) is formulated in the manner described herein (e.g., present in the compositions described herein). In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of cancer. In another certain embodiment, provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis. In yet another certain embodiment, provided herein are methods of treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder.

[0008] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description, examples, and claims.

Brief Description of the Drawings

[0009]

Figure 1

Modes for Carrying Out the Invention

[0010] In certain embodiments, the present disclosure provides, in certain embodiments, formula I

[0011]

Chemical Formula

[0012] Definitions The following are definitions of terms used herein. The first definition given for a group or term in this specification applies to that group or term throughout this specification, individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art.

[0013] As used herein, "a" or "an" can mean one or more. As used herein, "a" or "an" can mean one or more when used with the word "comprising". As used herein, "another" can mean at least a second or more. Further, the terms "having", "including", "containing", and "comprising" are interchangeable and are known to those of ordinary skill in the art to be open-ended terms. Some embodiments of the present invention can consist of or consist essentially of one or more elements, method steps, and / or methods of the present invention. It is contemplated that any method, compound, or composition described herein can be practiced in relation to any other method, compound, or composition described herein.

[0014] "About" and "approximately" generally mean an acceptable degree of error with respect to the measured quantity, taking into account the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%.

[0015] When a range of values is recited, it is intended to include each value and sub-range within that range. For example, "C 1-6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-6 alkyl, C 2-5 alkyl, C 2-4 alkyl, C 2-3 alkyl, C 3-6 alkyl, C 3-5 alkyl, C 3-4 alkyl, C 4-6 alkyl, C 4-5 alkyl, and C 5-6 alkyl.

[0016] The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the present invention.

[0017] "Alkyl" refers to a radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8"alkyl"). In some embodiments, the alkyl group has from 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has from 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., CH3). In certain embodiments, the alkyl group is substituted C 1-10It is alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0018] "Alkylene" refers to an alkyl group, which may be substituted or unsubstituted, from which two hydrogens have been removed to provide a divalent radical. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-). When a range or number of carbons is provided for a particular alkylene group, it is understood that this range or number refers to the range or number of carbons in the straight-chain carbon divalent chain. The alkylene group may be substituted with one or more substituents described herein or may be unsubstituted.

[0019] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom when the valence allows. The heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl") or a spiro ring system such as a fused ring system, a bridged ring system, or a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. The bicyclic heterocyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes, as defined above, a ring system in which the heterocyclyl ring is fused to one or more carbocyclic groups and the point of attachment is on the carbocyclic ring or the heterocyclyl ring, or, as defined above, a ring system in which the heterocyclyl ring is fused to one or more aryl groups or heteroaryl groups and the point of attachment is on the heterocyclyl ring. In such cases, the number of ring members continues to indicate the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each example of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted by one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0020] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0021] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiacanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0022] "Alkoxy" refers to an -OR' group, where R' is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., those having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0023] In certain embodiments, R' is amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-, and is a group having one or more substituents selected from the group consisting of, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t(4- to 10-membered heterocyclyl) is exemplified, but not limited thereto, where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0024] "Amino" or "amine" refers to the -NH2 radical.

[0025] "Oxo group" refers to -C(=O)-.

[0026] "Carboxy" refers to the -C(O)OH radical.

[0027] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is fluoro or chloro.

[0028] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc.

[0029] "Haloalkoxy" refers to an alkoxy radical in which the alkyl group is substituted with one or more halogens. Exemplary haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, chloromethoxy, dichloromethoxy, dibromomethoxy, tribromomethoxy, tetrafluoroethoxy, etc.

[0030] "Hydroxy" refers to the -OH radical.

[0031] "Benzyl" refers to the -CH2-C6H5 radical, which may be substituted or unsubstituted.

[0032] Unless otherwise indicated, any heteroatom that does not satisfy its valence shall be assumed to have hydrogen atoms sufficient to satisfy its valence.

[0033] It will be understood that the compounds described herein may be substituted by any number of substituents or functional moieties. In general, whether or not the term "optionally" precedes it, the term "substituted" and the substituents included in the formulas of the present invention refer to replacing a hydrogen radical in a given structure with a radical of a specific substituent. If multiple positions in any given structure may be substituted by multiple substituents selected from a specific group, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Heteroatoms such as nitrogen may have any acceptable substituents of the organic compounds described herein that satisfy the valence of the hydrogen substituents and / or the heteroatom. Furthermore, the present invention is not intended to be limited in any way by the acceptable substituents of organic compounds. The combinations of substituents and variables envisioned by the present invention preferably result in the formation of stable compounds, for example, useful for the treatment of infectious diseases or proliferative disorders. As used herein, the term "stable" preferably refers to a compound that has sufficient stability to allow for manufacture and maintains the integrity of the compound for a period sufficient to be detected, preferably for a period sufficient to be useful for the purposes detailed herein.

[0034] Certain compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (d) isomers, (l) isomers, their racemic mixtures, and other mixtures thereof, as being within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. It is intended that all such isomers, and mixtures thereof, are included in the present disclosure.

[0035] Stereoisomers of the compounds of the present invention, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbons on various substituents), are all contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a particular activity), or may be mixed, for example, as a racemate, or with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention may have an S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendation. Racemic forms can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by any suitable method including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

[0036] All configurational isomers of the compounds of the present disclosure are contemplated to be in the form of mixtures, or in pure or substantially pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon rings or heterocyclic rings.

[0037] Isomer mixtures containing any of various isomer ratios may be utilized in accordance with the present disclosure. For example, when only two isomers are used in combination, all mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present disclosure. Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomer mixtures as well.

[0038] In addition, the present disclosure includes isotopically labeled compounds, which are identical to the compounds disclosed herein except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes incorporable into the compounds of the present disclosure include, respectively 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc., isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Compounds of the present disclosure, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates, which contain the aforementioned isotopes and / or other isotopes of other atoms, are included within the scope of the present invention. Certain isotopically labeled compounds of the present disclosure, for example, 3 compounds incorporating radioactive isotopes such as 14 H and 3 H, and carbon-14 isotopes, i.e., 14 C, are useful for drug and / or substrate tissue distribution assays. Tritium isotopes, i.e., 2Substitution with heavier isotopes such as H provides certain therapeutic advantages resulting in higher metabolic stability, e.g., increased in vivo half-life or decreased required dose, and thus may be preferred in some situations. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents.

[0039] For example, if a particular enantiomer of a compound of the present disclosure is desired, this enantiomer can be prepared by asymmetric synthesis or by induction with a chiral auxiliary, in which case the resulting mixture of diastereomers is separated and the auxiliary is cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed using an appropriate optically active acid or base, and then the diastereomers so formed are resolved by fractional crystallization or chromatography methods well known in the art, and thereafter the pure enantiomer is recovered.

[0040] The compounds of the present disclosure are, after preparation, preferably isolated and purified to obtain a composition containing 90% or more, e.g., 95% or more, 99% or more by weight of the compound (a "substantially pure" compound), and this composition is then used or formulated as described herein. Such "substantially pure" compounds of the invention are also contemplated herein as part of the invention.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. have described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic acids and organic acids as well as inorganic bases and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods employed in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Examples of such salts include (alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0042] As used herein, "solvate" refers to a physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, for example, a solvate is isolable when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates can contain stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules results from partial loss of the solvent from the solvate. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, isopropanolates, and the like.

[0043] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin, but are not limited thereto.

[0044] As used herein, "subject" for which administration is contemplated includes humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or the elderly)), and / or non-human animals such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, mice, cats, and / or dogs), but is not limited thereto. 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 a healthcare provider.

[0045] Diseases, disorders, and illnesses are used interchangeably herein.

[0046] As used herein, unless otherwise defined, the terms "treat", "treating", and "treatment" contemplate acts that occur while a subject is suffering from a particular disease, disorder, or illness, and that reduce the severity of, reverse, or slow the progression of the disease, disorder, or illness (which is also a "therapeutic treatment").

[0047] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those of ordinary skill in the art, the effective amount of a compound of the present invention can vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health status, and disease of the subject. A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit (e.g., treating, preventing, and / or alleviating cancer in a subject) at a reasonable benefit / risk ratio applicable to any medical treatment in the treatment of a disease, disorder, or illness, or an amount sufficient to inhibit protein-protein interactions mediated by an SH2 domain in a subject, or an amount sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or illness. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or illness. The term "therapeutically effective amount" can include an amount that improves the overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or illness, or an amount that 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 illness, or one or more symptoms associated with the disease, disorder, or illness, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or illness. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis, or an amount that enhances the prophylactic efficacy of another prophylactic agent. "Prophylactic treatment" contemplates acts that occur before a subject begins to suffer from a particular disease, disorder, or illness.

[0048] As used herein, the term "STAT3 inhibitor" or "compound that inhibits STAT3" refers to a compound that inhibits the activity of STAT3 that functions one or more activities, including the ability of STAT3 to bind to a molecule such as a pY-peptide ligand and / or the ability to be phosphorylated.

[0049] As used herein, "TTI-101" refers to the following structure:

[0050]

Chemical formula

[0051] Compound TTI-101 is highly insoluble ("brick dust"). TTI-101 is insoluble in aqueous solutions and has relatively low solubility in most solvents. Further, TTI-101 has a crystal structure with high lattice energy, which contributes to the rapid precipitation or crystallization of the compound from solution. The low solubility and high crystallinity of TTI-101 have contributed to various difficulties in preparing a formulation suitable for administration to a human subject.

[0052] As used herein, in certain embodiments, compounds of Formula I are disclosed that provide high solubility (e.g., in aqueous solution) and stability at multiple pHs while maintaining pharmacokinetic properties equivalent to TTI-101 and showing improved chemical stabilization. In some embodiments, the compounds of Formula I have significantly improved chemical stability compared to ester (-O-C(O)) or carbonate (-O-C(O)-O-) based compounds of TTI-101.

[0053] In certain embodiments, Formula I:

[0054]

Chemical formula

[0055]

Chemical formula

[0056] In certain embodiments, R 3is H. In other embodiments, R 3 is C(=O)NR A R B In certain embodiments, R 3 is P(=O)(OH)(R c ) In certain embodiments, R 3 is C 1-4 alkylene-O-P(=O)(OH)(R c ) In certain embodiments, R 3 is H or C(=O)NR A R B In certain embodiments, R 3 is H or C(=O)NR A R B wherein R A is H and R B is C 1-6 alkylene-C(=O)OH optionally substituted by an amine.

[0057] In certain embodiments, R 1 is H. In other embodiments, R 1 is C(=O)NR A R B In certain embodiments, R 1 is P(=O)(OH)(R c ) In certain embodiments, R 1 is C 1-4 alkylene-O-P(=O)(OH)(R c ) In certain embodiments, R 1 is H, C(=O)NR A R B , or P(=O)(OH)(R c ) In certain embodiments, R 1 is H, C(=O)NR A R B wherein R A is H or methyl and R B is an amine, or C 1-6 alkylene-(5- to 6-membered heterocyclyl), or C 1-6Alkylene-N(H)(C 1-4 alkyl), C 1-6 is alkylene-C(=O)OH. In certain embodiments, R 1 is H, C(=O)NR A R B , where R A is H or methyl, and R B is an amine, or C 2-6 alkylene-(5-membered heterocyclyl), or C optionally substituted by P(=O)(OH)2 2-6 alkylene-N(H)(C 1-4 alkyl), C 2-6 is alkylene-C(=O)OH.

[0058] In certain embodiments, R 2 is H. In other embodiments, R 2 is C(=O)NR A R B . In certain embodiments, R 2 is P(=O)(OH)(R c ). In certain embodiments, R 2 is C 1-4 alkylene-O-P(=O)(OH)(R c ). In certain embodiments, R 2 is H, C(=O)NR A R B , or P(=O)(OH)(R c ). In certain embodiments, R 2 is H, C(=O)NR A R B , where R A is H or methyl, and R B is an amine, or C 1-6 alkylene-(5-6 membered heterocyclyl), or C optionally substituted by P(=O)(OH)2 1-6 alkylene-N(H)(C 1-4 alkyl), C 1-6 is alkylene-C(=O)OH. In certain embodiments, R 2 is H, C(=O)NR A RB and where R A is H or methyl, and R B is an amine, or C 2-6 alkylene-(5-membered heterocyclyl), or C optionally substituted by P(=O)(OH)2 2-6 alkylene-N(H)(C 1-4 alkyl), C 2-6 alkylene-C(=O)OH.

[0059] In certain embodiments, R 1 and R 2 together

[0060]

Chemical formula

[0061]

Chemical formula

[0062] In certain embodiments, R A is H or methyl. In certain embodiments, R A is H. In certain embodiments, R A is methyl.

[0063] In certain embodiments, R B is C 1-6 alkylene-N(H)(C 1-6 alkyl). In certain embodiments, R B is C 1-4 alkylene-N(H)(C 1-6 alkyl). In certain embodiments, R B is C 2-4 alkylene-N(H)(C 1-6 alkyl). In certain embodiments, R Bis CH2CH2N(H)(C 1-6 alkyl). In certain embodiments, R B is CH2CH2CH2N(H)(C 1-6 alkyl). In certain embodiments, R B is CH2CH2N(H)(CH3). In certain embodiments, R B is CH2CH2CH2N(H)(CH3).

[0064] In certain embodiments, R B is C 1-6 alkylene-(5- to 8-membered heterocyclyl). In certain embodiments, R B is C 1-4 alkylene-(5- to 8-membered heterocyclyl). In certain embodiments, R B is C 1-2 alkylene-(5- to 8-membered heterocyclyl). In certain embodiments, R B is C 1-6 alkylene-(5- to 8-membered heterocyclyl). In certain embodiments, R B is C 1-4 alkylene-(5- to 6-membered heterocyclyl). In certain embodiments, R B is C 1-2 alkylene-(5- to 6-membered heterocyclyl). In certain embodiments, R B is C 1-6 alkylene-(5-membered heterocyclyl). In certain embodiments, R B is C 1-4 alkylene-(5-membered heterocyclyl). In certain embodiments, R B is C 1-2 alkylene-(5-membered heterocyclyl). In certain embodiments, R B is C 1-4 alkylene-(5- to 8-membered N-containing heterocyclyl). In certain embodiments, R B is C 1-4 alkylene-(5- to 6-membered N-containing heterocyclyl). In certain embodiments, R B is C 1-4It is alkylene-(5-membered N-containing heterocyclyl). In certain embodiments, R B is C 1-2 It is alkylene-(5-membered heterocyclyl). In certain embodiments, R B is C 1-2 It is alkylene-(5- to 8-membered N-containing heterocyclyl). In certain embodiments, R B is C 1-2 It is alkylene-(5- to 6-membered N-containing heterocyclyl). In certain embodiments, R B is C 1-2 It is alkylene-(5-membered N-containing heterocyclyl).

[0065] In certain embodiments, R B is amine, C 1-4 alkyl, or C optionally substituted by benzyl 1-6 It is alkylene-C(=O)OH. In certain embodiments, R B is C substituted by amine 1-6 It is alkylene-C(=O)OH. In certain embodiments, R B is C substituted by amine 1-4 It is alkylene-C(=O)OH. In certain embodiments, R B is C substituted by amine 2-6 It is alkylene-C(=O)OH. In certain embodiments, R B is C substituted by amine 2-4 It is alkylene-C(=O)OH.

[0066] In certain embodiments, R C is C 1-4 alkyl. In some embodiments, R C is methyl. In other embodiments, R C is hydroxy.

[0067] In certain embodiments, A is halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4It is haloalkoxy. In certain embodiments, A is halo, C 1-4 alkyl, or C 1-4 alkoxy. In certain embodiments, A is C 1-4 alkoxy. In certain embodiments, A is methoxy.

[0068] In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0069] In certain embodiments, the compound is of formula I-A:

[0070]

Chemical formula

[0071] In certain embodiments, the compound is of formula I-B:

[0072]

Chemical formula

[0073] In certain embodiments, the compound is of formula I-C:

[0074]

Chemical formula

[0075] In certain embodiments, the compound is of formula I-D:

[0076]

Chemical formula

[0077] In certain embodiments, the compound is of formula I-E:

[0078]

Chem.

[0079] In certain embodiments, the compound is of formula I-F:

[0080]

Chem.

[0081] In certain embodiments, the compound is of formula I-G:

[0082]

Chem.

[0083] In certain embodiments, the compound is of formula I-H:

[0084]

Chem.

[0085] In certain embodiments, the compound is of formula I-I:

[0086]

Chem.

[0087] In certain embodiments, the compound is of formula I-J:

[0088]

Chem.

[0089] In certain embodiments, the compound is of formula I-K:

[0090]

Chem.

[0091] In certain embodiments, the compound is of formula I-L:

[0092]

Chem.

[0093] In certain embodiments, the compound is

[0094]

Chem.

[0095]

Chem.

[0096] In certain embodiments, the compound is

[0097]

Chem.

[0098]

Chem.

[0099] Pharmaceutical Compositions, Administration, and Dosage In certain embodiments, pharmaceutical compositions are provided herein that comprise a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0100] Accordingly, the present invention provides pharmaceutical compositions comprising, as an active ingredient, one or more of the described compounds or pharmaceutically acceptable salts or esters thereof, and a carrier comprising one or more pharmaceutically acceptable excipients, inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0101] The pharmaceutical compositions can be administered either by a single administration or multiple administrations, by any of the acceptable modes of drug administration, which have, for example, the same usefulness as those described in the patents and patent applications incorporated by reference herein, and the modes of administration include rectal, buccal, intranasal and transdermal routes, those by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated device or coating device such as a stent, or via an arterial insertion type cylindrical polymer.

[0102] One mode of administration is, in particular, the parenteral mode by injection. Forms in which the novel compositions of the present invention can be incorporated for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, and aqueous or oily suspensions or emulsions using elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline have also been conventionally used for injection, but are less preferred in the context of the present invention. Also, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can be used. Suitable fluidity can be maintained, for example, by using coating agents such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0103] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in an appropriate solvent, in the required amounts, together with the various other ingredients enumerated above as required, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion and the other necessary ingredients from those enumerated above. In the case of sterile powders for preparing sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, by which powders of the active ingredient and any additional desired ingredients are produced from a previously sterilized and filtered solution.

[0104] Oral administration is another route of administration for the compounds according to the present invention. The administration may be via, for example, capsules or enteric-coated tablets. When preparing a pharmaceutical composition containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier which can be in the form of capsules, sachets, wrappers or other containers. When the excipient functions as a diluent, this excipient can be in the form of a solid, semi-solid or liquid material (as described above) which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0105] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may further contain: lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxy-benzoates, sweetening agents, and flavoring agents.

[0106] The compositions of the present invention can be formulated to provide immediate release, sustained release, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Examples of controlled release pharmaceutical delivery systems for oral administration include osmotic pump systems and dissolution systems, including polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods of the present invention uses a transdermal delivery device (a "patch"). Such transdermal patches can be used to provide controlled amounts of continuous or discontinuous infusion of the compounds of the present invention. The construction and use of transdermal patches for delivering drugs are well known in the art. Such patches can be constructed for continuous delivery, pulsatile delivery, or demand-responsive delivery of the drug.

[0107] The composition is preferably formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human and other mammalian subjects, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients (e.g., tablets, capsules, ampoules). The compounds are usually administered in pharmaceutically effective amounts. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of the compounds described herein, and for parenteral administration, preferably from 0.1 to 1000 mg of the compounds described herein. However, it will be understood that the actual amount of the compound administered will usually be determined by the physician in light of the relevant circumstances, including the disease being 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, and the like.

[0108] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition that contains a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are homogeneous, it means that the active ingredient is evenly dispersed throughout the composition, and as a result, the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0109] The tablets or pills of the present invention may be coated or otherwise formulated in order to provide a dosage form that offers the advantage of long-term action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an internal administration component and an external administration component, and the external administration component is in the form of an envelope that covers the internal administration component. These two components may be separated by an enteric layer, which resists decomposition in the stomach and serves to allow the internal component to pass intact into the duodenum or to delay release. A variety of substances may be used for such an enteric layer or enteric coating, and such substances include numerous polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0110] Compositions for inhalation or insufflation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. The liquid or solid compositions may contain the appropriate pharmaceutically acceptable excipients described above. Preferably, the composition is administered by the oral or nasal respiratory route for local or systemic effects. Preferably, the composition in a pharmaceutically acceptable solvent can be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a facemask tent or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0111] In some embodiments, the composition comprising the compound of Formula I is administered to a subject as an oral dosage form. In some embodiments, the oral dosage form is in the form of a tablet. In some embodiments, the oral dosage form is in the form of a capsule.

[0112] The dosage may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's disease (see, e.g., Fingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”). Lower or higher dosages than those recited above may be required. The specific dosage and treatment regimen for any particular subject will vary depending on a variety of factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and course of the disease, disorder, or condition, the subject's susceptibility to the disease, disorder, or condition, and the judgment of the treating physician. The treatment course may include one or more separate administrations of the compounds described herein.

[0113] Method of Use The compounds and compositions described herein are utilized in methods for treating, preventing, or reducing the risk or severity of a disease or disorder mediated by STAT3, or alternatively a disease or disorder treatable with a STAT3 inhibitor. For example, the compounds and compositions are useful for treating, preventing, or reducing the risk or severity of a particular disease or disorder characterized by the overexpression of STAT3 protein. Such diseases and disorders include certain cancers, fibrosis, and inflammatory diseases / disorders.

[0114] In some embodiments, the method includes the use of a compound of formula (I), i.e., a STAT3 inhibitor (e.g., including administration), where the compound of formula (I) is formulated by the methods described herein (e.g., present in the compositions described herein). In certain embodiments, methods of treating, preventing, or reducing the risk or severity of cancer are provided herein. In another specific embodiment, methods of treating, preventing, or reducing the risk or severity of fibrosis are provided herein. In yet another specific embodiment, methods of treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder are provided herein.

[0115] Signal transducer and activator of transcription 3 (STAT3) is central in the regulation of the anti-tumor immune response. STAT3 is widely overactivated in both cancer cells and non-cancer cells within the tumor ecosystem and plays an important role in inhibiting the expression of key immunomodulatory factors and promoting the production of immunosuppressive factors. The methods provided herein are considered useful, for example, in the treatment of cancers including solid tumors, soft tissue tumors, and their metastases.

[0116] In certain embodiments herein, provided herein is a method of treating, preventing, or reducing the risk or severity of cancer in an individual in need of treatment of cancer, prevention of cancer, or reduction of the risk or severity of cancer, the method comprising administering to the individual the described compound or composition. 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, gastric cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone tumor, spleen cancer, gallbladder cancer, brain tumor, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disorder, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor positive breast cancer. In some embodiments, the cancer treated 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.

[0117] Furthermore, STAT3 is essential for the development of Th17 lymphocytes and cytokine production, and its activation has been associated with the development of airway inflammation. When activated, STAT3 is recruited to cytokine-activated receptor complexes and phosphorylated at Tyr (Y) 705. Phosphotyrosylated (p)STAT3 homodimerizes via SH2-pY705 interactions, translocates to the cell nucleus, and binds to promoters to transcriptionally activate genes that cause Th17 differentiation and the production of multiple cytokines. STAT3 activation is also involved in Th2 cytokine production and is a beneficial target for asthma treatment. Furthermore, several genes, including ATG16L, NOD2 / CARD15, IBD5, CTLA4, TNFSF15, JAK2, STAT3, IL23R, and ORMDL3, have been implicated as risk factors for inflammatory bowel disease (IBD) in genome-wide association studies (GWAS). These are involved in antimicrobial peptides, natural and acquired immune cell functions, Th17 cells, regulatory T cells (Tregs), and cytokines (tumor necrosis factor, interleukin 17, 23, 12, 22, and IL-6). Many of these cytokines function as ligands for cell surface receptors that activate STAT3. STAT3 in three cell lineages - myeloid cells, intestinal cells, and T cells - has been demonstrated to contribute to colitis in mice and humans. Therefore, targeting STAT3 may be an effective means for treating, preventing, or reducing the risk or severity of inflammatory diseases / disorders.

[0118] In certain embodiments of the present specification, there is provided a method of treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder in an individual in need of treatment, prevention, or reduction of the risk or severity of an inflammatory disease / disorder, the method comprising administering to the individual a compound or composition described herein. In some embodiments, the inflammatory disease / disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, allergy, cancer cachexia, chronic kidney disease cachexia, non-alcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis, multiple sclerosis, or pancreatitis. In some embodiments, the inflammation treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, allergy, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic steatohepatitis (NASH). In some embodiments, the allergy includes anaphylactic shock.

[0119] Fibrosis is a pathological process that involves the accumulation of excessive extracellular matrix in tissues, which can lead to tissue damage and organ dysfunction, and may progress to organ failure and death. Systemic sclerosis, which causes idiopathic fibrosis disease, is hypothesized to be an autoimmune response that causes tissue damage, production of growth factors, pro-inflammatory and profibrotic cytokines, and accumulation of myofibroblasts. Two causes that can give rise to myofibroblasts are the differentiation of local fibroblasts and the process of epithelial-mesenchymal transition (EMT). IL-6 is a pro-inflammatory and profibrotic cytokine that is increasingly recognized as an important mediator of fibrosis that can contribute to the accumulation of myofibroblasts. After engaging its receptor, IL-6 transmits signals via STAT3. Therefore, STAT3 may be an important protein that can be targeted for treating fibrosis.

[0120] In certain embodiments of the present specification, there is provided a method of treating, preventing, or reducing the risk or severity of fibrosis in an individual in need of treatment, prevention, or reduction of the risk or severity of fibrosis, the method comprising administering to the individual a compound or composition described herein. In certain embodiments, the fibrosis is associated with a disorder or disease such as cutaneous fibrosis (or dermal fibrosis), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, hepatic fibrosis, retroperitoneum, renal fibrosis, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse cutaneous systemic sclerosis or limited cutaneous systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrillation, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis. In certain embodiments, the fibrosis is associated with cutaneous fibrosis (scleroderma), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, hepatic fibrosis, retroperitoneum, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, the fibrosis is associated with cutaneous fibrosis (scleroderma), cardiac fibrosis, cirrhosis, or pulmonary fibrosis.

[0121] In certain embodiments, the fibrosis is associated with exposure to certain agents such as chemotherapy, fibrosis after exposure to environmental or other harmful substances or allergens, fibrosis that develops after ischemia / reperfusion injury such as myocardial infarction or hypotension, fibrosis that develops after radiotherapy, fibrosis after hepatitis induced by alcohol, harmful substances, drugs, or infection, primary biliary cirrhosis, fibrosis after viral infection including the heart, liver, or lung, and / or idiopathic retroperitoneal fibrosis.

[0122] Muscle wasting is a debilitating complication of catabolic states, including chronic kidney disease (CKD), diabetes, cancer, or severe infections. For example, in mice with CKD, inhibition of myostatin reduces the circulating levels of IL-6 and TNFα, suggesting an association between inflammation and muscle wasting as reported in clinical trials. STAT3 has been found to be activated by the IL-6 family of cytokines, and thus it is suggested that the STAT3 pathway is associated with a decrease in muscle mass.

[0123] In certain embodiments herein, a method of treating, preventing, or reducing the risk or severity of muscle wasting disease / disorder, muscle weakness disease / disorder, or cachexia in an individual in need thereof, the method comprising administering to the individual a compound or composition described herein. Muscle weakness and / or muscle wasting and / or cachexia may be idiopathic or associated with an underlying disease. The underlying disease may be a catabolic state. In some embodiments, the underlying disease associated with cachexia is at least kidney disease or renal insufficiency, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormonal deficiency, metabolic acidosis, infectious disease, chronic pancreatitis, autoimmune disorder, celiac disease, Crohn's disease, electrolyte disorder, Addison's disease, sepsis, burns, trauma, fever, long bone fracture, hyperthyroidism, long-term steroid treatment, surgery, bone marrow transplantation, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, tumor-associated syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dermatomyositis, rheumatic disease, autoimmune disease, collagen disease, visceral leishmaniasis, long-term bed rest, and / or dependence on drugs such as amphetamines, opioids, or barbiturates.

[0124] Furthermore, STAT3 signaling is involved in gap junction intercellular communication, IL-6- and IL11-induced vascular leakage, downregulation of VE-cadherin associated with phosphorylation of STAT3, and STAT3 / mir17-92 / E2F1-dependent regulation of β-catenin nuclear translocation and transcriptional activity. Thus, inhibition of STAT3 is useful for reducing vascular permeability in cases of allergy.

[0125] In certain embodiments herein, a method of treating, preventing, or reducing the risk or severity of an allergic reaction in an individual in need of treatment, prevention, or reduction of the risk or severity of an allergic reaction, the method comprising administering to the individual a compound or composition described herein is provided. In some embodiments, the allergic reaction is induced after exposure to an allergen. In some embodiments, the allergen is a food allergen (such as milk, legumes, crustaceans, nuts, eggs, fish, soy, and wheat), an environmental or seasonal allergen (such as pollen or mold), a venom allergen (such as those from wasps, bees, ants, hornets, yellow jackets, or Egyptian cobras), a drug allergen (such as an anesthetic, a β-lactam antibiotic, aspirin, a non-steroidal anti-inflammatory agent, chemotherapy, a vaccine, protamine, or a herbal preparation), or latex. In some embodiments, the allergic reaction is an allergy, anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenoptera allergy, bronchiolar constriction, asthma, or eczema.

[0126] In addition, STAT3 plays an important role in viral infections and viral pathogenicity. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of a viral infection in an individual in need of treatment, prevention, or reduction of the risk or severity of a viral infection, the method comprising administering to the individual a compound or composition described herein is provided. 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.

[0127] Furthermore, reactive astrocytes in neurodegenerative diseases including Alzheimer's disease are involved in the phosphorylation of STAT3. The pathophysiological role of astrocytes in the reactive state is thought to have important implications in the etiology of neurodegenerative diseases. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of a neurodegenerative disease in an individual in need of treatment, prevention, or reduction of the risk or severity of a neurodegenerative disease, the method comprising administering to the individual a compound or composition described herein is provided. In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemobrain. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of pain in an individual in need of treatment, prevention, or reduction of the risk or severity of pain, the method comprising administering to the individual a compound or composition described herein is provided. In some embodiments, the pain is neuropathic pain. In certain embodiments herein, a method for treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagas disease cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy is provided.

[0128] STAT3 is associated with cytokine- 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 II diabetes. In certain embodiments herein, a method of treating, preventing, or reducing the risk or severity of insulin resistance in an individual in need of treatment, prevention, or reduction of insulin resistance or its severity, the method comprising administering to the individual a compound or composition described herein is provided. In some embodiments, the insulin resistance results from an underlying condition. In some embodiments, the insulin resistance is associated with the muscle of the individual being treated. In some embodiments, the insulin resistance is caused by any cause of the individual, such as elevated free fatty acids in the blood, obesity, overweight, having visceral fat, high fructose intake, inflammation, inactivity, abnormal gut microbiota balance, and / or genetic predisposition. In certain embodiments, any method provided herein is a method of treating, preventing, or reducing the risk or severity of a medical condition associated with insulin resistance or a medical condition that is at least partially a complication of insulin resistance, such as severe hyperglycemia, severe hypoglycemia, heart attack, stroke, kidney disease (including chronic kidney disease (CKD)), eye disease, 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 feature of metabolic syndrome and type II diabetes. Metabolic syndrome is a cluster of risk factors associated with type II diabetes and heart disease. Its symptoms include elevated blood triglycerides, blood pressure, abdominal fat, and blood glucose levels, as well as low HDL (good) cholesterol levels.

[0129] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of the compositions disclosed herein. In certain embodiments, the method comprises administering to a subject at least 1 mg / kg per day of a compound of formula (I). In certain embodiments, the method comprises administering to a subject at least 10 mg / kg per day of a compound of formula (I). In certain embodiments, the method comprises administering to a subject at least 20 mg / kg per day of a compound of formula (I). In certain embodiments, the method comprises administering to a subject at least 25 mg / kg per day of a compound of formula (I).

Example

[0130] Abbreviations: As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples. g (gram), mg (milligram), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (molar), mM (millimolar), μmol (micromolar), μm (micron) MHz (megahertz), mm (millimeter) mol (mole), mmol (millimole), rt (room temperature), hr (hour), min (minute), THF (tetrahydrofuran), CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), atm (atmosphere), PE (petroleum ether) EtOAc (ethyl acetate), DCM (dichloromethane), EtOH (ethanol), t-Bu (tert-butyl), MeOH (methanol), ACN (acetonitrile), Na2SO4 (sodium sulfate), Boc (tert-butoxycarbonyl), MTBE (methyl tert-butyl ether), TFA (trifluoroacetic acid), HCl (hydrochloric acid), Et3N (triethylamine), DPPA (diphenylphosphoryl azide), POCl3 (phosphorus oxychloride), NaOH (sodium hydroxide), FA (formic acid)

[0131] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise stated, all reactions were carried out at room temperature. 1 1H-NMR spectra were recorded on a Bruker 400 or Varian Unity-400 at a magnetic field strength of 400 MHz. Chemical shifts are expressed in parts per million (ppm, δ units). The splitting pattern describes the apparent multiplicity and is designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), quin (quintet), or br (broad). Mass spectra were performed on a Sciex API 100 using electrospray ionization (ESI). LC / MS was performed using a C-18 reverse-phase column (2.1 ID, 3.5 micron, 50 mm). Purity was confirmed and the progress of the reaction was monitored using thin layer chromatography. Unless otherwise indicated, all final products were at least 95% pure as determined by HPLC / MS.

[0132] Example 1. Synthesis of Compounds Exemplary compounds of Formula I were prepared according to the following method.

[0133] 1'-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalene]-2-ylmethyl (2-(methylamino)ethyl)carbamate hydrochloride (Compound 3) Step 1. Tert-butyl (2-((chlorocarbonyl)(methyl)amino)ethyl)(methyl)carbamate.

[0134]

Chem.

[0135] Step 2. tert-Butyl (1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-2-yl)ethane-1,2-diylbis(methylcarbamate) To a solution of tert-butyl (2-((chlorocarbonyl)(methyl)amino)ethyl)(methyl)carbamate (6 g, 23.93 mmol, 1 eq) in pyridine (60 mL) was added N-(1',2-dihydroxy-[1,2'-binaphthalen]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (3.39 g, 7.18 mmol, 0.3 eq) at room temperature. The resulting solution was then heated to 40 °C and stirred for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with 1.0 M HCl (1 x 200 mL), brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1~1:1) to give the title compound (3.5 g, yield 20%) as a solid. C 37 H 39 LCMS calculated value for C28H31N3O8S: m / z = 686, found: m / z = 709 (M+Na).

[0136] Step 3: 1'-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-2-ylmethyl (2-(methylamino)ethyl)carbamate hydrochloride. Tert-butyl (1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-2-yl)ethane-1,2-diylbis(methylcarbamate) (3.5 g, 5.10 mmol, 1 equiv) was dissolved in 4N HCl / EtOAc (40 mL), and the resulting reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was then diluted with MTBE (100 mL). The reaction mixture was then filtered. The recovered solid was slurried in acetone (15 mL), warmed to 50 °C, and stirred for 30 min, during which time the solid dissolved to form a clear solution. The solution was then cooled to 0 °C and stirred for 2 h, during which time a precipitate formed. The resulting suspension was filtered to recover the solid. The solid was then dried under high vacuum to obtain the title compound (1.56 g, 47% yield) as a solid. 1 H NMR (400 MHz, methanol-d4) δ = 8.32 (m, 1H), 8.14 (m, 3H), 7.66 (m, 2H), 7.44 (m, 5H), 7.29 (m, 1H), 6.84 (m, 3H), 3.38 (s, 3H), 3.42 - 3.32 (m, 2H), 2.84 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 2.13 (s, 3H). C 32 H 31 Calculated for C28H28N3O6S: m / z = 585; found: m / z = 586 (M + H).

[0137] 2-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-ylmethyl (3-(methylamino)propyl)carbamate hydrochloride (Compound 4)

[0138]

Chemical Structure

[0139] Step 2: Tert-butyl (2-((chlorocarbonyl)(methyl)amino)propyl)(methyl)carbamate. To a solution of tert-butyl N-methyl-N-(3-(methylamino)propyl)carbamate (6.0 g, 29.66 mmol, 1.0 eq) in pyridine (60 mL), bis(trichloromethyl) carbonate (3.52 g, 11.86 mmol, 0.4 eq) was added at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to give the title compound as a solid, which was used immediately in the next step.

[0140] Step 3: Tert-butyl (2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalene]-1'-yl)propane-1,2-diylbis(methylcarbamate). A solution of N-(1’,2-dihydroxy-[1,2’-binaphthalen]-4’-yl)-4-methoxybenzenesulfonamide (TTI-101) (4.27 g, 9.07 mmol, 0.3 eq) in pyridine (100 mL) was added with tert-butyl (2-((chlorocarbonyl)(methyl)amino)propyl)(methyl)carbamate (8 g, 30.22 mmol, 1.0 eq) at room temperature. Subsequently, the resulting reaction mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in H2O (200 mL), and the mixture was adjusted to pH 2 by adding 1 M HCl. Then, the aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1~1:1) to obtain the title compound (4.4 g, yield 18%) as a solid. C 38 H 41 Calculated LCMS value for C31H31N3O8S: m / z = 700, measured value: m / z = 723 (M+Na).

[0141] Step 4: 2-Hydroxy-4’-((4-methoxyphenyl)sulfonamido)-[1,2’-binaphthalen]-1’-yl methyl (3-(methylamino)propyl)carbamate hydrochloride. A solution of tert-butyl (2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yl)propane-1,2-diylbis(methylcarbamate) (4.4 g, 6.29 mmol, 1.0 eq) in EtOAc (40 mL) was added 4N HCl / EtOAc (20 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by preparative reverse-phase HPLC (Phenomenex Luna C18 column (250x70 mmx15 μm), mobile phase: [water (0.04% HCl)-ACN], B%: 14% - 44%, 20 min) to give 3 g of the substance. The substance was added to acetone (30 mL) and heated to 50 °C with stirring for 30 min, during which the solid dissolved to form a clear solution. The solution was then cooled to 0 °C and stirred for 2 h, during which a precipitate formed. The resulting suspension was filtered to recover the solid. The solid was then dried under high vacuum to give the title compound (1.4 g, 36% yield) as a solid. 1 H NMR: (400 MHz, methanol-d4) δ = 8.28 (m, 1H), 8.14 (m, 1H), 8.00 (m, 2H), 7.68 - 7.48 (m, 5H), 7.43 - 7.21 (m, 3H), 6.85 (m, 3H), 3.70 (s, 3H), 3.29 - 3.13 (m, 2H), 2.84 (m, 1H), 2.70 (s, 3H), 2.58 (m, 2H), 2.47 (m, 1H), 2.28 (m, 1H), 1.68 - 1.52 (m, 2H). The position of the carbamate positional isomers was not clearly confirmed by NMR spectroscopy. C 33 H 33 LCMS calculated value for C27H27N3O6S: m / z = 599, found: m / z = 600 (M+).

[0142] (2S)-2-Amino-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yl)oxy)carbonyl)amino)butanoic acid hydrochloride (Compound 6A, 6B, 6C).

[0143]

Chemical formula

[0144] Process 2: (2S)-2-Amino-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yl)oxy)carbonyl)amino)butanoic acid hydrochloride. A solution of tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yloxy)carbonyl)amino)butanoate (4.8 g, 6.22 mmol, 1.0 eq) in DCM (50 mL) was added with TFA (14.18 g, 124.37 mmol, 9.21 mL, 20 eq) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse-phase HPLC (Phenomenex Luna C18 column (250x70 mmx15 μm), mobile phase: [water (0.04% HCl)-ACN], B%: 25% - 30%, 20 min) to obtain three isomers. They were randomly assigned as isomeric compounds 6A, 6B, and 6C. Isomer 6A: 600 mg, solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.03 (s, 1H), 9.49 (s, br, 1H), 8.29 (m, 1H), 8.18 (m, 2H), 7.78 (m, 3H), 7.70 - 7.55 (m, 5H), 7.21 (m, 3H), 6.98 (m, 3H), 6.77 (s, 1H), 3.63 (m, 4H), 2.90 (m, 2H), 1.76 (m, 1H), 1.62 (m, 2H), C 32 H 29 LCMS calculated value for C19H19N3O8S: m / z = 615, measured value: m / z = 616 (M + H). Isomer 6B: 640 mg, solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.05 (s, 1H), 9.49 (s, br, 1H), 8.29 (m, 4H), 7.78 (m, 3H), 7.61 (m, 5H), 7.25 (m, 3H), 6.98 (m, 3H), 6.78 (s, 1H), 3.77 (m, 1H), 3.61 (s, 3H), 2.95 (m, 2H), 1.29 (m, 2H), C 32 H 29 LCMS calculated value for C19H19N3O8S: m / z = 615, measured value: m / z = 616 (M + H). Isomer 6C: 850 mg, solid. 11H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.07 (s, 1H), 8.23 (m, 4H), 7.98 (m, 3H), 7.57 - 7.41 (m, 9H), 7.19 (m, 1H), 6.98 (dd, J = 8.8, 2H), 6.75 (s, 1H), 3.89 (m, 1H), 3.69 (s, 3H), 3.18 (m, 2H), 1.90 (m, 2H). C 32 H 29 LCMS calculated value for C18H13N3O8S: m / z = 615; found: m / z = 616 (M + H).

[0145] N-((6)-6-Hydroxy-6-oxido dinaphtho[1,2-d:1’,2’-f][1,3,2]dioxaphosphepin-15-yl)-4-methoxybenzenesulfonamide (Compound 9A), and 2-hydroxy-4’-((4-methoxyphenyl)sulfonamido)-[1,2’-binaphthalene]-1’-yl dihydrogen phosphate (Compound 9).

[0146]

Chem.

[0147] Step 2: 2-Hydroxy-4’-((4-methoxyphenyl)sulfonamido)-[1,2’-binaphthalen]-1’-yl dihydrogen phosphate. A solution of N-((6)-6-hydroxy-6-oxido dinaphtho[1,2-d:1’,2’-f][1,3,2]dioxaphosphepin-15-yl)-4-methoxybenzenesulfonamide (2 g, 3.75 mmol, 1.0 equivalent) in NaOH (1 M, 11.25 mL, 3.0 equivalents) was heated to 80 °C with stirring for 3 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (Welch Xtimate C18 250x70mmx10μm column, mobile phase: [H2O (10 mM NH4HCO3)-ACN], B%: 3% - 30%, 25 min) to give 650 mg of the product. The product was added to EtOH / i-PrOH (5 mL, 1:3). The resulting slurry was stirred and heated to 50 °C over 30 min, during which the solid completely dissolved to form a clear solution. The solution was then cooled to 0 °C and stirred for 2 h, during which a precipitate formed. The resulting suspension was filtered to recover the solid. The solid was then dried under high vacuum to give the title compound (160 mg, 22% yield) as a solid. 1 H NMR: (400 MHz, methanol-d4) δ = 8.62 (d, 1H), 8.19 (d, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.49 (m, 4H), 7.24 (m, 2H), 7.11 (d, 1H), 6.77 (d, 2H), 6.59 (d, 1H), 6.40 (s, 1H), 3.62 (m, 3H). C 27 H 22 LCMS calculated value for NO8PS: m / z = 551, measured value: m / z = 552 (M + H).

[0148] 2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yl(((R)-pyrrolidin-2-yl)methyl)carbamate (Compound 15A and 15B).

[0149]

Chemical Structure

[0150] Project 2: 2-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yl ((R)-pyrrolidin-2-yl)methyl carbamate hydrochloride. To a solution of tert-butyl (2R)-2-(((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthalen]-1'-yloxy)carbonyl)amino)methyl)pyrrolidine-1-carboxylate (4.8 g, 6.88 mmol, 1.0 eq) in DCM (50 mL), TFA (15.69 g, 137.58 mmol, 10.19 mL, 20 eq) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (Phenomenex Luna C18 (250x70mmx15μm column), mobile phase: [H20(0.04%HCl)-ACN], B%: 16% - 46%, 20 minutes) to obtain the title compound as two isomers, which were randomly assigned as Compound 15A and 15B. Subsequently, Isomer 15A was triturated with acetone:ACN (30 mL, 1:1), and the resulting solid was isolated by filtration and dried under high vacuum to obtain 1.2 g of the substance as a solid. 1 H NMR (400 MHz, methanol-d4) δ = 8.24 (m, 1H), 7.98 (m, 3H), 7.58 (m, 2H), 7.54 - 7.41 (m, 5H), 7.30 (m, 1H), 6.92 (m, 3H), 3.69 (s, 3H), 3.46 - 3.09 (m, 3H), 3.02 (m, 2H), 1.67 (m, 3H), 1.27 (m, 1H), C 33 H 31 Calculated LCMS value for C29H27N3O6S: m / z = 597, measured value: m / z = 598 (M+H). Subsequently, Isomer 15B was added to acetone:EtOAc (20 mL, 1:1). The resulting slurry was stirred and heated to 50 °C over 30 minutes, during which the solid completely dissolved and a solution was formed. The solution was then cooled to 0 °C and stirred for 2 hours, during which a precipitate formed. The resulting suspension was filtered to recover the solid. The solid was then dried under high vacuum to obtain 400 mg of the substance as a solid. 11H NMR (400 MHz, DMSO-d6) δ = 10.03 (s, br, 1H), 9.49 (m, 1H), 9.06 - 8.67 (s, br, 1H), 8.23 (m, 2H), 7.86 - 7.59 (m, 8H), 7.22 (m, 3H), 6.93 (m, 3H), 6.77 (m, 1H), 3.71 (s, 3H), 3.27 - 3.07 (m, 2H), 3.04 - 2.86 (m, 2H), 1.69 - 1.22 (m, 3H), 1.10 - 0.83 (m, 1H), C 33 H 31 Calculated LCMS value for N3O6S: m / z = 597, Measured value: m / z = 598 (M + H).

[0151] The following compounds:

[0152]

Chemical formula

[0153] Example 2. Solubility, human plasma stability, and aqueous solution stability of the compounds The solubility, plasma stability, and aqueous solution stability of the compounds were evaluated (Table 1).

[0154]

Table 1

[0155] Aqueous solution stability For Compound 3, Compound 4, Compound 6A, Compound 6B, Compound 6C, Compound 15A, Compound 15B: For each compound, 10 μL of a 10 mM DMSO stock solution was added to 490 μL of DMSO to obtain a 200 μM working solution. Then, 2 μL of the 200 μM working solution was added to 96 deep well plates corresponding to T0, T60, T120, T360, and T1440. Then, 198 μL of a 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) solution was added to the corresponding wells except for T0, such that the final test concentration at each time point (60 minutes, 120 minutes, 360 minutes, 1440 minutes) was 2 μM. The final concentration of DMSO in the incubation mixture was 1%. The samples were incubated at 37 °C and 600 rpm for the specified time. The test samples at the corresponding time points (60 minutes, 120 minutes, 360 minutes, 1440 minutes) were removed at the end of the incubation time and immediately mixed with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol (internal standard) and 0.3% FA. Then, 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol and 0.3% FA. After adding 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol and 0.3% FA, 198 μL of a 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) was transferred to the corresponding wells to prepare the T0 sample. Then, 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol and 0.3% FA. The samples were centrifuged at 4000 rpm and 4 °C for 20 minutes, 60 μL of the supernatant was pipetted and mixed with 180 μL of purified water, and used for LC / MS / MS analysis. The percentage of the test compound remaining at each incubation time was calculated based on the peak area ratio of analyte / IS:

[0156]

Number

[0157] For Compound 9 and Compound 9A: For each compound, 10 μL of a 10 mM DMSO stock solution was added to 490 μL of DMSO to obtain a 200 μM working solution. Then, 2 μL of the 200 μM working solution was added to 96-deep well plates corresponding to T0, T60, T120, T360, and T1440. Then, 198 μL of a 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) solution was added to the corresponding wells except for T0, such that the final test concentration at each time point (60 minutes, 120 minutes, 360 minutes, 1440 minutes) was 2 μM. The final concentration of DMSO in the incubation mixture was 1%. The samples were incubated at 37 °C and 600 rpm for the specified time. The test samples at the corresponding time points (60 minutes, 120 minutes, 360 minutes, 1440 minutes) were removed at the end of the incubation time and immediately mixed with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol (internal standard). Then, 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol. After adding 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol, 198 μL of a 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) was transferred to the corresponding wells to prepare the T0 sample. Then, 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL of tolbutamide and labetalol. The samples were centrifuged at 4000 rpm and 4 °C for 20 minutes, and 60 μL of the supernatant was pipetted and mixed with 180 μL of purified water for LC / MS / MS analysis. The percentage of the test compound remaining at each incubation time was calculated based on the analyte / IS peak area ratio.

[0158] Solubility For each compound, a supersaturated suspension was obtained by adding 450 μL of 75 mM phosphate buffer (pH 2.0 and 7.4). The mixture was vortexed for at least 2 minutes. The samples were shaken at 800 rpm for 24 hours at room temperature and then centrifuged. The suspension was filtered through a PTFE filter medium. The filtrate was analyzed by HPLC (column: Waters XBridge C18 4.6*100M, mobile phase A: 0.1% TFA in water, mobile phase B: 0.1% TFA in acetonitrile), and the concentration was calculated using a standard curve.

[0159] Plasma stability 98 μL / well of blank plasma was added to all 96-well reaction plates (blank, T0, T10, T30, T60, and T120). A working solution (100 μM) of each compound at 2 μL / well was added to all reaction plates except the blank. All reaction plates containing the mixture of the compound and plasma were incubated in a water bath at 37 °C. At the end of the incubation, proteins were precipitated by adding 400 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in ACN, optionally 0.1% FA), shaken, and centrifuged. The supernatant was analyzed by LC-MS / MS.

[0160] Example 3. Pharmacokinetics of Compounds in Mice, Rats, and Monkeys The pharmacokinetics of TTI-101 and the compounds of formula I were evaluated in rats after a single intravenous (IV) bolus of TTI-101 and oral (PO) gavage of the compounds of formula I.

[0161] In four tests, 24 male Sprague-Dawley rats were divided into four groups of 6 animals / group. Animals in Group 1 were administered TTI-101 at 21.5 mg / kg by single IV bolus. Animals in Groups 2, 3, and 4 were administered Compound 3, Compound 4, and Compound 9, respectively, at doses equivalent to 17.8 mg / kg, 18.1 mg / kg, and 19.2 mg / kg of TTI-101 by single PO administration. Plasma samples were collected before dosing (0), at 0.083 h (IV only), 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. The concentration of TTI-101 in plasma samples was determined by LC-MS / MS. The vehicle used in the IV test was DMSO / EtOH / PEG400 / saline (5 / 2 / 43 / 50 % v / v). The vehicle used in the PO test was 0.5% methylcellulose (400 cps) in 50 mM citrate buffer, pH approximately 3.5, or PBS, pH approximately 7.4.

[0162] Furthermore, TTI-101 administered orally as a self-emulsifying drug dispersion (SEDD) prepared according to the method described in International Publication No. WO2021 / 150912 showed F% = 40.4 in rats.

[0163] Table 2 shows exemplary PK data of the compounds of Formula I in rats.

[0164]

Table 2

[0165] The pharmacokinetics of TTI-101 and the compounds of Formula I were evaluated in monkeys after single intravenous (IV) bolus or oral (PO) gavage of TTI-101 and oral (PO) gavage of the compounds of Formula I.

[0166] A group of three male cynomolgus monkeys was used in this 5-phase study. The animals in Phase 1 were administered TTI-101 at 26 mg / kg by single intravenous bolus injection. The animals in Phases 2, 3, 4, and 5 were administered TTI-101 SEDD, Compound 3, Compound 9A, and Compound 9, respectively, by single oral administration. Plasma samples were collected for Phases 1, 2, 3, 4, and 5 at pre-dose (0), 0.083 hours post-dose (Phase 1 only), 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (excluding Phase 1). The concentration of TTI-101 in the plasma samples was determined by LC-MS / MS. The SEDD formulation of TTI-101 was prepared according to the method described in International Application No. WO2021 / 150912.

[0167] Table 3 shows exemplary PK data of the compounds of Formula I in monkeys.

[0168]

Table 3

[0169] H22 (HCC model) syngeneic mice were orally treated twice daily with Compound 9 (e.g., 34 mg / kg, 69 mg / kg, and 103 mg / kg in PBS, which are 25 mg / kg, 50 mg / kg, and 75 mg / kg TTI-101 equivalents, respectively) and TTI-101 SEDD (e.g., 50 mg / kg). Figure 1 shows the exposure profiles comparing Compound 9 and TTI-101 SEDD. Figure 1 shows that Compound 9 has more than 3-fold the exposure of TTI-101 SEDD in mice by day 21.

Claims

1. Formula I: 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt or solvate thereof, wherein the formula is A is Halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, or C １－４ It is a haloalkoxy, R １ 、 R ２ 、 and R ３ are each independently H, C(=O)NR Ａ R Ｂ , P(=O)(OH)(R Ｃ ), or C １－４ alkylene - O - P(=O)(OH)(R Ｃ ), or alternatively R １ and R ２ They became one 【Chemistry 2】 Forming, However, R １ , R ２ , and R ３ It is not H at the same time, R Ａ is H or C １－４ It is alkyl, R Ｂ is amine, C １－４ C optionally substituted with alkyl or benzyl １－６ Alkylene-N(H)(C) １－６ Alkyl), C １－６ Alkilen-(5-8 member heterocyclyl), C １－６ It is alkylene-C(=O)OH R Ｃ C １－４ Alkyl or hydroxy, n is an integer of 0, 1, 2, or 3, and is a compound or a pharmaceutically acceptable salt or solvate thereof.

2. R ３ The compound according to claim 1, wherein H is present, or a pharmaceutically acceptable salt or solvate thereof.

3. R ３ C(=O)NR Ａ R Ｂ The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

4. R １ The compound according to claim 1, wherein H is present, or a pharmaceutically acceptable salt or solvate thereof.

5. R １ and R ２ But, as one 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, which forms [the compound].

6. R ２ C(=O)NR Ａ R Ｂ The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

7. R ２ P(=O)(OH)(R ｃ The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

8. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

9. The compound is of formula I-A: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound according to claim 9 or a pharmaceutically acceptable salt or solvate thereof, wherein A is C1-4 alkoxy.

11. The compound is of formula I-G: 【Transformation 5】 The compound according to claim 10, or a pharmaceutically acceptable salt or solvate thereof.

12. The compound is of formula I-H or formula I-K: 【Transformation 6】 The compound according to claim 11, or a pharmaceutically acceptable salt or solvate thereof.

13. The compound is of formula I-B: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound is of formula I-E: 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

15. The compound is 【Chemistry 9-1】 【Chemistry 9-2】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound is 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

17. A pharmaceutical composition comprising: a) a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof; and b) a pharmaceutically acceptable carrier.

18. A pharmaceutical composition for use in a method of treating cancer in an individual requiring treatment for cancer, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

19. The pharmaceutical composition according to claim 18, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone tumor, spleen cancer, gallbladder cancer, brain tumor, pancreatic cancer, stomach cancer, anal cancer, multiple myeloma, post-transplant lymphoproliferative disorder, restenosis, myelodysplastic syndrome, leukemia, or lymphoma.

20. The pharmaceutical composition according to claim 18, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer.

21. A pharmaceutical composition for use in a method of treating fibrosis in an individual requiring treatment for fibrosis, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

22. The pharmaceutical composition according to claim 21, wherein the fibrosis is pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, articular fibrosis, hepatic fibrosis, retroperitoneal fibrosis, renal fibrosis, bone marrow fibrosis, dermal fibrosis, or systemic sclerosis.

23. A pharmaceutical composition for use in a method of treating an inflammatory disease or disorder in an individual requiring treatment of an inflammatory disease or disorder, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

24. The pharmaceutical composition according to claim 23, wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleraitis, multiple sclerosis, pancreatitis, or asthma.

25. A pharmaceutical composition for use in a method of treating a neurodegenerative disease or disorder in an individual requiring treatment of a neurodegenerative disease or disorder, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

26. The pharmaceutical composition according to claim 25, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy.

27. ​​A pharmaceutical composition for use in a method of treating non-alcoholic fatty liver disease or steatohepatitis in an individual requiring treatment for non-alcoholic fatty liver disease or steatohepatitis, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

28. A pharmaceutical composition for use in a method for treating cachexia in an individual requiring treatment of cachexia, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

29. A pharmaceutical composition for use in a method for treating hypersensitivity in an individual requiring treatment for hypersensitivity, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof.

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