Prodrugs of STAT3 inhibitors

Abstract

Provided herein, in certain embodiments, are compounds of Formula I: # imgabs0 # (I) or a pharmaceutically acceptable salt or solvate thereof, compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and uses thereof, e.g., in the treatment of a disease or disorder (e.g., cancer, fibrosis, chronic inflammation).

Description

[0001] Cross-references This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 366,437, filed on June 15, 2022, the entire contents of which are incorporated herein by reference. Summary of the invention

[0002] In certain embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts or solvates thereof, and compositions comprising compounds of Formula I or pharmaceutically acceptable salts or solvates thereof and pharmaceutically acceptable carriers. In certain embodiments, the compounds and compositions disclosed herein are effective in inhibiting signal transducer and activator of transcription 3 (STAT3), and thus can be used in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer, fibrosis, and inflammatory diseases or disorders).

[0003] In certain embodiments, provided herein are compounds of Formula I:

[0004] (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; R 1 , R 2 , and R 3 Each independently is H, C(=O)NR A R B 、P(=O)(OH)(R C ), or C 1-4 Alkylene-OP(=O)(OH)(R C );or R 1 and R 2 Together they form: ; The premise is R 1 , R 2 , and R 3 Not at the same time H; R A Is H or C 1-4 alkyl; R B It is C 1-6 Alkylene-N(H)(C 1-6 Alkyl), C 1-6 Alkylene-(5-8 membered heterocyclic group), C1-6 Alkylene-C(=O)OH, optionally amine, C 1-4 Alkyl or benzyl substitution; R C It is C 1-4 Alkyl or hydroxyl; and n is an integer of 0, 1, 2, or 3.

[0005] In certain embodiments, provided herein are pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0006] In certain embodiments, provided herein are methods involving the use of (e.g., comprising administering) a compound of formula (I) (a STAT3 inhibitor), wherein the compound of formula (I) is formulated in a manner described herein (e.g., present in a composition as described herein). In specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of cancer. In other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of fibrosis. In other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of inflammatory diseases / disorders.

[0007] Other objects and advantages will become apparent to those skilled in the art after consideration of the following detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 Shown is the exposure comparison of TTI-101 SEDD and Compound 9 (in PBS) in H22 syngeneic mice. DETAILED DESCRIPTION

[0009] In certain embodiments, the present disclosure provides compounds of Formula I:

[0010] (I) Or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising 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 of the present disclosure can effectively inhibit signal transducer and activator of transcription 3 (STAT3). Therefore, in certain embodiments, the present disclosure also provides the use of such compounds and compositions in methods for treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer, fibrosis, and inflammatory diseases or disorders).

[0011] definition The following are definitions of terms used in this specification. Unless otherwise specified, the initial definition provided herein for a group or term applies to the group or term used alone or as part of another group throughout the specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0012] As used in this specification, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising", "a" may mean one or more than one. As used herein, "another" may mean at least a second or more. In addition, the terms "having", "including", "containing" and "comprising" are interchangeable and those skilled in the art know that these terms are open terms. Some embodiments of the present invention may 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 may be implemented together with any other method, compound, or composition described herein.

[0013] "About" and "approximately" generally refer to an acceptable degree of error for the quantity measured, depending on the nature or precision of the measurement. An exemplary degree of error is within twenty percent (20%), typically within 10%, and more typically within 5% of a given value or range of values.

[0014] When a numerical range is listed, it is intended to include every value and sub-range within that range. For example, "C 1-6 "Alkyl" means C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.

[0015] The following terms are intended to have the meanings presented below and may aid in understanding the description and intended scope of the present invention.

[0016] "Alkyl" refers to a group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 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), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each example of alkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, alkyl is unsubstituted C 1-10 In some embodiments, the alkyl group is substituted with C 1-10 Alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0017] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups (e.g., 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—), and the like. When a range or number of carbon atoms is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbon atoms in its linear divalent carbon chain. As described herein, an alkylene group may be unsubstituted or substituted with one or more substituents as described herein.

[0018] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocycle / heterocyclyl"). In heterocyclic radicals containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. The heterocycle may be a single ring ("monocyclic heterocycle") or a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic heterocycle"), and may be saturated or may be partially unsaturated. Heterocyclic bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclic rings, wherein the point of attachment is on the carbocyclic or heterocyclic ring, or a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, in which case the number of ring members still refers to the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclyl”) or substituted (“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0019] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocycle / heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0020] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclic groups fused to a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclic groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0021] "Alkoxy" refers to the group -OR', where R' is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

[0022] In certain embodiments, R' is a group having 1 or more substituents, such as 1 to 5 substituents, particularly 1 to 3 substituents, and especially 1 substituent, selected from the group consisting of amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, mercapto, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6-C 10 Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10 Cycloalkyl), and -O-(CH2) t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl present may itself be substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or hydroxy. Particular exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0023] "Amino" or "amine" refers to the radical -NH2.

[0024] "Carbonyl" refers to -C(=O)-.

[0025] "Carboxyl" refers to the radical -C(O)OH.

[0026] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halo group is fluorine or chlorine.

[0027] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0028] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens. Typical haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, chloromethoxy, dichloromethoxy, dibromoethoxy, tribromomethoxy, tetrafluoroethoxy, and the like.

[0029] "Hydroxyl" refers to the radical -OH.

[0030] "Benzyl" refers to the radical -CH2-C6H5 and may be substituted or unsubstituted.

[0031] Unless otherwise stated, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0032] It is understood that the compounds described herein may be substituted with any number of substituents or functional groups. In general, the term "substituted / substituted" (whether or not preceded by the term "optionally") and the substituents contained in the formulae of the present invention refer to the replacement of hydrogen radicals in a given structure with a specifically designated substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specifically designated group, the substituents at each position may be the same or different. As used herein, the term "substituted / substituted" is considered to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatoms. In addition, the present invention is not intended to be limited in any way to permissible substituents of organic compounds. The combinations and variations of substituents contemplated by the present invention are preferably combinations and variations that form stable compounds useful for treating, for example, infectious diseases or proliferative disorders. As used herein, the term "stable" preferably refers to a compound that is sufficiently stable to facilitate manufacture and retains the integrity of the compound for a sufficient period of time to facilitate detection, and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0033] Certain compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present invention contemplates that all such compounds (including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof) fall within the scope of the present disclosure. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are intended to be included in the present disclosure.

[0034] All stereoisomers of the compounds of the present invention (e.g., due to asymmetric carbons on various substituents) (including enantiomeric and diastereomeric forms) are considered to fall within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers with a specific activity), or may be mixed, for example, as racemates or mixed with all other or selected other stereoisomers. The chiral centers of the present invention may have an S configuration or an R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) in 1974. The racemic forms may be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from racemates by any suitable method, including but not limited to conventional methods, such as forming a salt with an optically active acid and then crystallizing.

[0035] All configurational isomers of the disclosed compounds are contemplated, whether in mixture or in pure or substantially pure form. The definition of the compounds of the present invention encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomeric forms of cyclic hydrocarbons or heterocycles.

[0036] According to the content of the present disclosure, isomer mixtures containing any of various isomer ratios can be used. For example, in the case of combining only two isomers, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all considered by the present disclosure. It will be readily understood by those of ordinary skill in the art that similar ratios are considered for more complex isomer mixtures.

[0037] The present disclosure also includes isotopically labeled compounds, which are identical to the compounds disclosed herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18F. and 36 Cl. Compounds of the present disclosure or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof containing the aforementioned isotopes and / or other isotopes of other atoms fall within the scope of the present invention. Certain isotopically labeled compounds of the present disclosure (e.g., radioactive isotopes (e.g., 3 H and 14 C) into which it is incorporated) can be used for tissue distribution determination of drugs and / or substances. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because they are easy to prepare and detect. In addition, heavier isotopes (such as deuterium, i.e. 2 H) Substitutions may be preferred in some circumstances due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage leading to certain therapeutic advantages). In general, isotopically labeled compounds can be prepared by carrying out the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0038] For example, if a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the formed diastereomers by fractional crystallization or chromatography as is well known in the art, and then the pure enantiomer is recovered.

[0039] After preparation, the compounds disclosed herein are preferably isolated and purified to obtain a composition containing an amount by weight of equal to or greater than 90%, such as equal to or greater than 95%, equal to or greater than 99% of the compound ("substantially pure" compound), and then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also considered part of the present invention.

[0040] As used herein, "pharmaceutically acceptable salts" means salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. J. Pharmaceutical Sciences(1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 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 1-4 Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower carbon alkyl sulfonates and aryl sulfonates, where appropriate.

[0041] As used herein, "solvate" refers to a physical combination of a compound and one or more solvent molecules (organic or inorganic). This physical combination includes hydrogen bonding. In some instances, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecules may result from a partial loss of solvent from the solvate. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, isopropanolates, and the like.

[0042] 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 in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0043] As used herein, the "subject" intended to be administered includes, but is not limited to, humans, i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, teenagers) or adult subjects (e.g., young adults, middle-aged people, or the elderly) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," "subject," and "individual" are interchangeable herein. None of these terms require active supervision by medical personnel.

[0044] Disease, disorder and condition are used interchangeably herein.

[0045] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to an action that occurs in a subject suffering from a particular disease, disorder, or condition that reduces the severity of, or reverses or slows the progression of, the disease, disorder, or condition (also referred to as "therapeutic treatment").

[0046] In general, the "effective amount" of a compound refers to an amount sufficient to cause a desired biological response. As will be understood by those of ordinary skill in the art, the effective amount of the compounds disclosed herein may vary according to factors such as the expected biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health, and condition of the subject. The "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition (e.g., to treat, prevent, and / or improve cancer in a subject, or to inhibit protein-protein interactions mediated by SH2 domains in a subject at a reasonable benefit / risk ratio applicable to any medical treatment), or sufficient to delay or alleviate one or more symptoms associated with a disease, disorder, or condition. The therapeutically effective amount of a compound refers to an amount of a therapeutic agent (used alone or in combination with other therapies) that provides a therapeutic benefit when treating a disease disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves the overall therapeutic effect, alleviates or avoids the symptoms or causes of a disease or condition, or enhances the efficacy of another therapeutic agent. A "prophylactically effective amount" of a compound refers to an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent (used alone or in combination with other agents) that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" may encompass an amount that can improve the overall prophylactic effect or enhance the prophylactic efficacy of another prophylactic agent. "Prophylactic treatment" contemplates treatment performed before a subject begins to suffer from a particular disease, disorder, or condition.

[0047] As used herein, a "STAT3 inhibitor" or a compound that "inhibits STAT3" refers to a compound that interferes with one or more activities of STAT3, including the ability of STAT3 to bind to and / or phosphorylate a molecule such as a pY-peptide ligand.

[0048] As used herein, "TTI-101" refers to the compound having the following structure: .

[0049] Compound TTI-101 is highly insoluble ("brick dust"). It is insoluble in aqueous solutions and has relatively low solubility in most solvents. It also has a crystalline structure with high lattice energy, which facilitates rapid precipitation or crystallization of the compound from solution. Its low solubility and high crystallinity present difficulties in preparing formulations suitable for administration to human subjects.

[0050] In certain embodiments, the compounds of Formula I disclosed herein have high solubility (e.g., in aqueous solution) and stability at various pHs, and exhibit better chemical stability while maintaining similar pharmacokinetic properties to TTI-101. In some embodiments, the compounds of Formula I have significantly improved chemical stability compared to ester (-OC(O)) or carbonate (-OC(O)-O-) compounds of TTI-101.

[0051] In certain embodiments, provided herein are compounds of Formula I:

[0052] (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; R 1 , R 2 and R 3 Each independently is H, C(=O)NR A R B 、P(=O)(OH)(R C ), or C 1-4 Alkylene-OP(=O)(OH)(R C );or R 1 and R 2 Together they form: ; The premise is R 1 , R 2 and R 3 Not at the same time H; R A Is H or C 1-4 alkyl; R B It is C 1-6 Alkylene-N(H)(C 1-6 Alkyl), C 1-6 Alkylene-(5-8 membered heterocyclic group), C 1-6 Alkylene-C(=O)OH, optionally amine, C 1-4 Alkyl or benzyl substitution; R C It is C 1-4 Alkyl or hydroxyl; and n is an integer of 0, 1, 2, or 3.

[0053] In certain embodiments, R3 is H. In other embodiments, R 3 It is C(=O)NR A R B In certain embodiments, R 3 It is P(=O)(OH)(R C ). In certain embodiments, R 3 It is C 1-4 Alkylene-OP(=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 , where R A is H and R B is C optionally substituted with an amine 1-6 Alkylene-C(=O)OH.

[0054] In certain embodiments, R 1 is H. In other embodiments, R 1 It is C(=O)NR A R B In certain embodiments, R 1 It is P(=O)(OH)(R C ). In certain embodiments, R 1 It is C 1-4 Alkylene-OP(=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 , where R A is H or methyl and R B It is C 1-6 Alkylene-N(H)(C 1-4 alkyl), optionally substituted by amine 1-6 Alkylene-C(=O)OH, or C 1-6 alkylene-(5-6 membered heterocyclyl), or P(=O)(OH)2. In certain embodiments, R 1 is H, C(=O)NR A R B , where R A is H or methyl and RB It is C 2-6 Alkylene-N(H)(C 1-4 alkyl), optionally substituted by amine 2-6 Alkylene-C(=O)OH, or C 2-6 Alkylene-(5-membered heterocyclic group), or P(=O)(OH)2.

[0055] In certain embodiments, R 2 is H. In other embodiments, R 2 It is C(=O)NR A R B In certain embodiments, R 2 It is P(=O)(OH)(R C ). In certain embodiments, R 2 It is C 1-4 Alkylene-OP(=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 It is C 1-6 Alkylene-N(H)(C 1-4 alkyl), optionally substituted by amine 1-6 Alkylene-C(=O)OH, or C 1-6 alkylene-(5-6 membered heterocyclyl), or P(=O)(OH)2. In certain embodiments, R 2 is H, C(=O)NR A R B , where R A is H or methyl and R B It is C 2-6 Alkylene-N(H)(C 1-4 alkyl), optionally substituted by amine 2-6 Alkylene-C(=O)OH, or C 2-6 Alkylene-(5-membered heterocyclic group), or P(=O)(OH)2.

[0056] In certain embodiments, R 1 and R 2 Together they form: In certain embodiments, R 1 and R 2 Together they form: , where R C It's OH.

[0057] In certain embodiments, R A is H or methyl. In certain embodiments, R A is H. In certain embodiments, R A It's methyl.

[0058] In certain embodiments, R B It is C 1-6 Alkylene-N(H)(C 1-6 In certain embodiments, R B It is C 1-4 Alkylene-N(H)(C 1-6 In certain embodiments, R B It is C 2-4 Alkylene-N(H)(C 1-6 In certain embodiments, R B is CH2CH2N(H)(C 1-6 In certain embodiments, R B is CH2CH2CH2N(H)(C 1-6 In certain embodiments, R B is CH2CH2N(H)(CH3). In certain embodiments, R B It is CH2CH2CH2N(H)(CH3).

[0059] In certain embodiments, R B It is C 1-6 In certain embodiments, R B It is C 1-4 In certain embodiments, R B It is C 1-2 In certain embodiments, R B It is C 1-6 In certain embodiments, R B It is C 1-4 In certain embodiments, R B It is C 1-2 In certain embodiments, R B It is C 1-6 In certain embodiments, R B It is C 1-4 In certain embodiments, RB It is C 1-2 In certain embodiments, R B It is C 1-4 Alkylene-(5-8 membered N-containing heterocyclic group). In certain embodiments, R B It is C 1-4 Alkylene-(5-6 membered N-containing heterocyclic group). In certain embodiments, R B It is C 1-4 In certain embodiments, R B It is C 1-2 In certain embodiments, R B It is C 1-2 Alkylene-(5-8 membered N-containing heterocyclic group). In certain embodiments, R B It is C 1-2 Alkylene-(5-6 membered N-containing heterocyclic group). In certain embodiments, R B It is C 1-2 Alkylene-(5-membered N-containing heterocyclic group).

[0060] In certain embodiments, R B It is C 1-6 Alkylene-C(=O)OH, optionally amine, C 1-4 In certain embodiments, R B is C substituted by amine 1-6 In certain embodiments, R B is C substituted by amine 1-4 In certain embodiments, R B is C substituted by amine 2-6 In certain embodiments, R B is C substituted by amine 2-4 Alkylene-C(=O)OH.

[0061] In certain embodiments, R C It is C 1-4 In some embodiments, R C In other embodiments, R C It's a hydroxyl group.

[0062] In certain embodiments, A is halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 In certain embodiments, A is halogen, C 1-4Alkyl, or C 1-4 In certain embodiments, A is C 1-4 Alkoxy. In certain embodiments, A is methoxy.

[0063] 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.

[0064] In certain embodiments, the compound is a compound of Formula IA:

[0065] (IA) or a pharmaceutically acceptable salt or solvate thereof.

[0066] In certain embodiments, the compound is a compound of Formula IB:

[0067] (IB) or a pharmaceutically acceptable salt or solvate thereof.

[0068] In certain embodiments, the compound is a compound of Formula IC:

[0069] (IC) or a pharmaceutically acceptable salt or solvate thereof.

[0070] In certain embodiments, the compound is of Formula ID:

[0071] (ID) or a pharmaceutically acceptable salt or solvate thereof.

[0072] In certain embodiments, the compound is a compound of Formula IE:

[0073] (IE) or a pharmaceutically acceptable salt or solvate thereof.

[0074] In certain embodiments, the compound is a compound of Formula IF:

[0075] (IF) or a pharmaceutically acceptable salt or solvate thereof.

[0076] In certain embodiments, the compound is a compound of formula IG:

[0077] (IG) or a pharmaceutically acceptable salt or solvate thereof.

[0078] In certain embodiments, the compound is a compound of Formula IH:

[0079] (IH) or a pharmaceutically acceptable salt or solvate thereof.

[0080] In certain embodiments, the compound is a compound of Formula II:

[0081] (II) or a pharmaceutically acceptable salt or solvate thereof.

[0082] In certain embodiments, the compound is a compound of Formula IJ:

[0083] (IJ) or a pharmaceutically acceptable salt or solvate thereof.

[0084] In certain embodiments, the compound is a compound of Formula IK:

[0085] (IK) or a pharmaceutically acceptable salt or solvate thereof.

[0086] In certain embodiments, the compound is a compound of Formula IL:

[0087] (IL) or a pharmaceutically acceptable salt or solvate thereof.

[0088] In certain embodiments, the compound is: , , , , , , , , , , ,or , or a pharmaceutically acceptable salt or solvate thereof.

[0089] In certain embodiments, the compound is: , , , , , , , , , ,or .

[0090] Pharmaceutical compositions, administration and dosage In certain embodiments, the pharmaceutical compositions provided herein comprise a compound as described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0091] Therefore, the pharmaceutical composition provided by the present invention contains one or more of the compounds or their pharmaceutically acceptable salts or esters as active ingredients, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, cosolvents and adjuvants. These pharmaceutical compositions can be used alone or in combination with other therapeutic agents. The preparation method of such compositions is well known in the field of pharmaceutical technology (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker & C. T. Rhodes, editor)).

[0092] The pharmaceutical composition can be administered in single or multiple doses by any recognized mode of administration with similar utility, for example, the modes of administration described in the patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenous administration, intraperitoneal administration, parenteral administration, intramuscular administration, subcutaneous administration, oral administration, topical administration, administration as an inhalant, or by administration via an impregnated or coated device (such as a stent or a cylindrical polymer inserted into an artery).

[0093] A mode of administration is parenteral administration, particularly injection administration. The novel composition of the present invention can be used for injection administration in the form of aqueous or oily suspension or emulsion formed with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixir, mannitol, dextrose, or sterile aqueous solution, and similar drug media. Saline solution is a commonly used injection, but is not preferred in the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and their suitable mixtures), cyclodextrin derivatives and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating (such as lecithin), by maintaining the required particle size (in the case of dispersion) and by using a surfactant. The effect of preventing microorganisms can be achieved by various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0094] Sterile injection is prepared by adding the required amount of the compound of the present invention together with the various other ingredients listed above to an appropriate solvent and then filtering and sterilizing. Generally speaking, the preparation method of the dispersant is to add various sterilized active ingredients to a sterile medium, which contains a basic dispersion medium and the required other ingredients listed above. For sterile powders for the preparation of sterile injection, the preferred preparation methods are vacuum drying and freeze drying techniques, which can obtain powders of active ingredients and other required ingredients from previously sterile filtered solutions.

[0095] According to the present invention, oral administration is another route for administering the compound. Administration can be by capsules or enteric coated tablets, etc. When manufacturing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted by an excipient and / or contained in a carrier in the form of a capsule, a sachet, paper, or other container. When the excipient acts as a diluent, it can be in the form of a solid, semisolid, or liquid material (such as above), acting as a vehicle, carrier, or medium for the active ingredient. Therefore, these compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injections, and sterile packaged powders.

[0096] Examples of some suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. These preparations may also include: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0097] The compositions of the present invention can be prepared by using procedures known in the art so that the active ingredient is released quickly, continuously or delayed after being applied to the patient. The controlled release drug delivery system for oral administration includes an osmotic pump system and a dissolution system, which contains a storage material or a drug-polymer matrix preparation through a polymer coating. Another preparation used in the method of the present invention adopts a transdermal delivery device ("patch"). Such a transdermal patch can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in a controlled amount. The construction and use of a transdermal patch for delivering a pharmaceutical agent are well known in the art. Such a patch can be constructed to be used for continuous, pulsatile or on-demand delivery of a medicament.

[0098] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units that are suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and combined with a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). These compounds are generally administered in a pharmaceutically effective amount. For oral administration, each dosage unit preferably contains from 1 mg to 2 g of the compound described herein, and for parenteral administration, each dosage unit preferably contains from 0.1 mg to 1000 mg of the compound described herein. However, it should be understood that the amount of the compound actually administered will usually be determined by the doctor according to relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight and individual response of the patient, the severity of the patient's symptoms, and the like.

[0099] To prepare solid compositions (such as tablets), the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition, which is a uniform mixture containing the compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0100] The tablet or pill of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to provide a dosage form that is free from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being encapsulated and covering the former. The two components can be separated by an enteric layer, which is used to prevent it from disintegrating in the stomach and allows the inner component to enter the duodenum intact or to delay release. Various materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0101] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Such liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route to achieve local or systemic efficacy. Compositions in preferred pharmaceutically acceptable solvents may be atomized by use of an inert gas. Atomized solutions may be inhaled directly from a spray device or the spray device may be attached to a mask or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered (preferably orally or nasally) from a device that delivers the formulation in an appropriate manner.

[0102] In some embodiments, the composition comprising a compound of Formula I is administered to the subject in the form of 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.

[0103] The dosage may vary based on the dosage form used and the route of administration used. The specific formulation, route of administration and dosage may be selected by the doctor according to the patient's condition. (See, for example, Fingl et al., 1975, The Pharmacological Basis of Therapeutics). Lower or higher doses than the above doses may be required. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, sex, diet, administration time, excretion frequency, drug combination, severity and course of disease, disorder or symptom, the subject's tendency to suffer from the disease, disorder or symptom, and the judgment of the attending physician. The course of treatment may include one or more separate administrations of the compound as described herein.

[0104] How to use The compounds and compositions described herein can be used to treat, prevent, or reduce the risk or severity of a disease or disorder mediated by STAT3, or a method of reducing the risk or severity of a disease or disorder that can be treated by a STAT3 inhibitor. For example, these compounds and compositions can be used to treat, prevent, or reduce the risk or severity of certain diseases or disorders characterized by overexpression of STAT3 protein. Such diseases and disorders include certain cancers, fibrosis, and inflammatory diseases / disorders.

[0105] In some embodiments, the method involves using (e.g., comprising administering) a compound of formula (I) (a STAT3 inhibitor), wherein the compound of formula (I) is formulated as described herein (e.g., present in a composition as described herein). In specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of cancer. In other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of fibrosis. In other specific embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of inflammatory diseases / disorders.

[0106] Signal transducer and activator of transcription 3 (STAT3) is central to regulating anti-tumor immune responses. STAT3 is widely hyperactivated in both cancer cells and non-cancerous cells in the tumor ecosystem and plays an important role in inhibiting the expression of key immune activation regulators and promoting the production of immunosuppressive factors. The methods provided herein can be used to treat cancer, including, for example, solid tumors, soft tissue tumors, and metastases thereof.

[0107] In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of cancer in a subject in need thereof, the method comprising administering to the subject a compound or composition as described herein. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor-positive breast cancer. In some embodiments, the cancer treated 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.

[0108] In addition, STAT3 is essential for the development of Th17 lymphocytes and the production of cytokines, and its activation is associated with the development of respiratory inflammation. After activation, STAT3 is immediately recruited to the cytokine-activated receptor complex and phosphorylated at Tyr(Y)705. Tyrosine phosphorylated (p) STAT3 forms homodimers through the corresponding SH2-pY705 interaction, transports to the nucleus, and binds to the promoter to transcriptionally activate genes, thereby promoting Th17 differentiation and the production of multiple cytokines. STAT3 activation is also involved in the production of Th2 cytokines, making it an attractive target for the treatment of asthma. In addition, several genes have been implicated as risk factors for inflammatory bowel disease (IBD) in genome-wide association studies (GWAS), including ATG16L, NOD2 / CARD15, IBD5, CTLA4, TNFSF15, JAK2, STAT3, IL23R, and ORMDL3, which affect antimicrobial peptides, innate and adaptive immune cell functions, Th17 cells, regulatory T cells (Treg), and cytokines (tumor necrosis factor, interleukins 17, 23, 12, 22, and IL-6). Many of these cytokines are ligands for cell surface receptors that activate STAT3. STAT3 in three cell lines (myeloid cells, intestinal epithelial cells, and T cells) has been shown to cause colitis in mice and humans. Therefore, targeting STAT3 may be an effective approach to treat, prevent, or reduce the risk or severity of inflammatory diseases / disorders.

[0109] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder in a subject in need thereof, the method comprising administering a compound or composition as described herein to the subject. In some embodiments, the inflammatory disease / disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, non-alcoholic fatty liver disease (NASH), psoriasis, uveitis, scleritis, multiple sclerosis, or pancreatitis. In some embodiments, the inflammation treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic fatty liver disease (NASH). In some embodiments, the allergic reaction comprises anaphylactic shock.

[0110] Fibrosis is a pathological process that involves the accumulation of excess extracellular matrix in tissues, leading to tissue damage and organ dysfunction, which progresses to organ failure and death. Systemic sclerosis is an idiopathic fibrotic disease, the cause of which is presumed to be an autoimmune response, which leads to tissue damage, the production of growth factors, proinflammatory cytokines and profibrotic cytokines, and the accumulation of myofibroblasts. Two potential sources of myofibroblasts are local fibroblast differentiation and the epithelial to mesenchymal transition (EMT) process. IL-6 is a proinflammatory and profibrotic cytokine that is increasingly recognized as an important mediator of fibrosis, which can contribute to the accumulation of myofibroblasts. After binding to its receptor, IL-6 signals through STAT3. Therefore, STAT3 represents an important potential target protein for the treatment of fibrosis.

[0111]

[0013] Certain embodiments herein provide methods of treating, preventing, or reducing the risk or severity of fibrosis in a subject in need thereof, the method comprising administering to the subject a compound or composition described herein. In certain embodiments, the fibrosis is associated with a disorder or disease such as skin fibrosis (or dermal fibrosis), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bonemarrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneum, kidney fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or limited systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis. In certain embodiments, fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, or pulmonary fibrosis.

[0112] In certain embodiments, the fibrosis is associated with exposure to certain drugs (such as chemotherapy), is fibrosis following exposure to environmental or other toxins or allergens, fibrosis occurring after ischemia / reperfusion injury (such as myocardial infarction or hypotension), fibrosis occurring after radiation, fibrosis following hepatitis induced by alcohol, toxins, drugs, or infection, primary biliary cirrhosis, fibrosis following viral infection involving the heart, liver, or lungs, and / or idiopathic retroperitoneal fibrosis.

[0113] Muscle wasting is a debilitating complication of metabolic diseases including chronic kidney disease (CKD), diabetes, cancer or severe infection. For example, in mice with CKD, inhibition of myostatin reduced circulating levels of IL-6 and TNFα, suggesting a link between inflammation and muscle wasting, as reported in clinical studies. Studies have shown that STAT3 is activated by the IL-6 family of cytokines, suggesting that the STAT3 pathway is involved in the loss of muscle mass.

[0114] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of a muscle wasting disease / disorder, a muscle weakness disease / disorder, or cachexia in a subject in need thereof, the method comprising administering to the subject a compound or composition as described herein. The possible cause of the muscle weakness and / or muscle atrophy and / or cachexia is unknown, or it may be related to an underlying condition. The underlying condition may be a metabolic condition. In some embodiments, the underlying condition associated with cachexia is leastrenal disease or failure, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormone deficiency, metabolic acidosis, infectious disease, chronic pancreatitis, autoimmune disease, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever, long bone fractures, hyperthyroidism, long-term steroid therapy, surgery, bone marrow transplantation, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome, syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dematomyositis, rheumatic diseases, autoimmune diseases, collagen vascular diseases, visceral leishmaniasis, prolonged bed rest, and / or drug addiction (such as amphetamines, opioids, or barbitutates).

[0115] In addition, STAT3 signaling has been implicated in gap junction intercellular communication, IL-6 and IL11-induced vascular leakage, VE-cadherin downregulation concomitant with STAT3 phosphorylation, and STAT3 / mir17-92 / E2F1-dependent regulation of β-catenin nuclear translocation and transcriptional activity. Therefore, STAT3 inhibition could be used to reduce vascular permeability in allergic reactions.

[0116] In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of an allergic reaction in a subject in need thereof, the method comprising administering to the subject a compound or composition as described herein. In some embodiments, the allergic reaction is induced after exposure to an allergen. In some embodiments, the allergen is a food allergen (such as milk, beans, shellfish, tree nuts, eggs, fish, soy, and wheat), an environmental allergen or a seasonal allergen (such as pollen or mold), a venom allergen (such as from a wasp, bee, ant, hornet, yellow jacket, or asp), a drug allergen (such as an anesthetic, β-lactam antibiotic, aspirin, nonsteroidal anti-inflammatory drugs, chemotherapy, vaccines, protamine, or herbal preparations) or latex. In some embodiments, the allergic reaction is anaphylaxis, anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenoptera allergy, bronchoconstriction, asthma, or eczema.

[0117] STAT3 also plays an important role in viral infection and pathogenesis. In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of viral infection in a subject in need thereof, the method comprising administering to the subject any compound or composition described herein. 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.

[0118] In addition, reactive astrocytes in neurodegenerative diseases (including Alzheimer's disease) are associated with STAT3 phosphorylation. The pathophysiological effects of astrocytes in a reactive state are considered to be of great significance in the pathogenesis of neurodegenerative diseases. Provided herein in certain embodiments are methods for treating, preventing, or reducing the risk or severity of a neurodegenerative disease in a subject in need, the method comprising administering a compound or composition as described herein to the subject. In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemo-brain. In certain embodiments, provided herein are methods for treating, preventing, or reducing the risk or severity of pain in a subject in need, the method comprising administering a compound or composition as described herein to the subject. In some embodiments, pain is neuropathic pain. In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagasic cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

[0119] STAT3 is involved in cytokine and nutrient-induced insulin resistance, and excessive STAT3 signaling is associated with the generation of insulin resistance, such as skeletal muscle insulin resistance in type 2 diabetes. Certain embodiments herein provide a method for treating, preventing or reducing the risk or severity of insulin resistance in a subject in need thereof, the method comprising administering a compound or composition as described herein to the subject. In some embodiments, the insulin resistance is the result of an underlying condition. In some embodiments, the insulin resistance is associated with the muscle of the subject being treated. In some embodiments, the insulin resistance is caused by any cause of the subject (such as elevated free fatty acids in the blood, obesity, overweight, visceral fat, high fructose intake, inflammation, being inactive, intestinal flora imbalance, and / or genetic predisposition). In certain embodiments, any of the methods provided herein are methods of treating, preventing, or reducing the risk or severity of a medical condition associated with, or at least in part a complication of, insulin resistance, such as severe hyperglycemia; severe hypoglycemia; heart disease; stroke; kidney disease (including chronic, such as 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, the insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes. Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Its symptoms include high blood triglycerides, high blood pressure, abdominal obesity, and high blood sugar, as well as low high-density lipoprotein (HDL) (good) cholesterol levels.

[0120] In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of a composition disclosed herein. In certain embodiments, the method comprises administering to the subject at least 1 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the subject at least 10 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the subject at least 20 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the subject at least 25 mg / kg / day of a compound of formula (I).

[0121] Example abbreviation: The symbols and conventions used in these processes, procedures and examples used herein are consistent with those used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). In particular, the following abbreviations may be used in the examples:

[0122] Unless otherwise stated, all temperatures are in °C (Celsius). Unless otherwise stated, all reactions were performed at room temperature. 1 H-NMR spectra were recorded on a Bruker 400 or Varian Unity-400 at 400 MHz field strength. Chemical shifts are expressed in parts per million (ppm, delta units). Splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), quin (pentapert), 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 μm, 50 mm). Analytical thin layer chromatography was used to verify purity and follow the progress of reactions. Unless otherwise stated, all final products were judged to be at least 95% pure by HPLC / MS.

[0123] Example 1. Synthesis of compounds Exemplary compounds of Formula I were prepared according to the following methods.

[0124] Methyl (2-(methylamino)ethyl)carbamic acid 1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-2-yl ester hydrochloride (Compound 3)

[0125] Step 1. tert-Butyl (2-((chlorocarbonyl)(methyl)amino)ethyl)(methyl)carbamate.

[0126] At 0°C, N -methyl- NTo a solution of tert-butyl-[2-(methylamino)ethyl]carbamate (5.0 g, 26.56 mmol, 1.0 eq) in pyridine (50 mL) was added di(trichloromethyl)carbonate (3.15 g, 10.62 mmol, 0.4 eq). The resulting reaction mixture was warmed to rt and stirred for 3 hr. The reaction mixture was then concentrated under reduced pressure to give the title compound as a solid, which was immediately used in the next step.

[0127] Step 2. Ethane-1,2-diyl bis(methylcarbamate) tert-butyl(1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-2-yl)ester.

[0128] 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'-binaphthyl]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (3.39 g, 7.18 mmol, 0.3 eq). The resulting solution was then heated to 40°C and stirred for 12 hr. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with 1.0 M HCl (1×200 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound as a solid (3.5 g, yield 20%). For C 37 H 39 LCMS calculated for N3O8S: m / z = 686; found: m / z = 709 (M+Na).

[0129] Step 3: 1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-2-yl methyl(2-(methylamino)ethyl)carbamate hydrochloride.

[0130] Tert-butyl (1'-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-2-yl) 1,2-diyl bis(methylcarbamate) (3.5 g, 5.10 mmol, 1 eq) was dissolved in 4 N HCl / EtOAc (40 mL) and the resulting reaction mixture was stirred at rt for 0.5 hr. The reaction mixture was then diluted with MTBE (100 mL). The reaction mixture was then filtered. The collected solid was slurried with 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 hr, during which time a precipitate formed. The resulting suspension was filtered and the solid was collected. The solid was then dried under high vacuum to give the title compound as a solid (1.56 g, 47% yield). 1 H NMR (400MHz, Methanol-d4) δ = 8.32(m, 1H), 8.14 (m, 3H), 7.66 (m, 2H), 7.44 (m, 5 H), 7.29 (m, 1 H), 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). For C 32 H 31 LCMS calculated for N3O6S: m / z = 585; found: m / z = 586 (M+H).

[0131] Methyl (3-(methylamino)propyl)carbamic acid 2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl ester hydrochloride (Compound 4)

[0132] Step 1: N -methyl- N -tert-Butyl (3-(methylamino)propyl)carbamate.

[0133] At 0°C, N , N’To a solution of 1-dimethylpropane-1,3-diamine (5.0 g, 48.93 mmol, 1.0 eq) in DCM (100 mL) was added a solution of di-tert-butyl dicarbonate (4.27 g, 19.57 mmol, 4.50 mL, 0.4 eq) in DCM (80 mL). The resulting reaction mixture was warmed to rt and stirred for 12 hr. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in H2O (300 mL) and extracted with PE (2×150 mL). The aqueous phase was then extracted with DCM (5×200 mL). The combined DCM layers were washed with brine (1×300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (8.1 g, 27% yield) as an oil. 1 H NMR: (400MHz, CDCl3) δ = 3.21 (m, 2H), 2.77 (s, 3H), 2.49(t, J = 6.8, 2H), 2.37 (m, 4H), 1.60 (m, 2H), 1.39 (s, 9H). Step 2: tert-Butyl (2-((chlorocarbonyl)(methyl)amino)propyl)(methyl)carbamate.

[0134] At 0°C, N -methyl- N To a solution of tert-butyl-(3-(methylamino)propyl)carbamate (6.0 g, 29.66 mmol, 1.0 eq) in pyridine (60 mL) was added di(trichloromethyl)carbonate (3.52 g, 11.86 mmol, 0.4 eq). The resulting reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to give the title compound as a solid, which was immediately used in the next step.

[0135] Step 3: Propane-1,2-diyl bis(methylcarbamate) tert-butyl(2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)ester.

[0136] rt, to NTo a solution of -(1',2-dihydroxy-[1,2'-binaphthyl]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (4.27 g, 9.07 mmol, 0.3 eq) in pyridine (100 mL) was added tert-butyl (2-((chlorocarbonyl)(methyl)amino)propyl)(methyl)carbamate (8 g, 30.22 mmol, 1.0 eq). The resulting reaction mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in H2O (200 mL) and 1M HCl was added to adjust the pH of the mixture to 2. The aqueous solution was then extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (1×250 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 to 1:1) to give the title compound (4.4 g, 18% yield) as a solid. 38 H 41 LCMS calculated for N3O8S: m / z = 700; found: m / z = 723 (M+Na).

[0137] Step 4: 2-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl methyl(3-(methylamino)propyl)carbamate hydrochloride.

[0138] To a solution of propane-1,2-diylbis(methylcarbamic acid)tert-butyl(2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)ester (4.4 g, 6.29 mmol, 1.0 eq) in EtOAc (40 mL) was added 4 N HCl / EtOAc (20 mL) at rt. The resulting reaction mixture was stirred at rt for 1 hr. 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 (250×70 mm×15 µm); mobile phase: [water (0.04% HCl)-ACN]; B%: 14%-44%, 20 min) to give 3 g of material. The material was added to acetone (30 mL) and heated to 50 °C with stirring 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 hr, during which time a precipitate formed. The resulting suspension was filtered to collect the solid. The solid was then dried under high vacuum to afford the title compound as a solid (1.4 g, 36% yield). 1H NMR: (400MHz,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 regioisomeric location of the carbamate was not clearly determined by NMR spectroscopy. 33 H 33 LCMS calculated for N3O6S: m / z = 599; found: m / z = 600 (M+).

[0139] (2S)-2-Amino-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)butyric acid hydrochloride (Compounds 6A, 6B, 6C).

[0140]

[0141] Step 1: tert-Butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)butanoate.

[0142] To a solution of (4S)-5-tert-butoxy-4-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid (1.0 g, 3.30 mmol, 1.0 eq) in toluene (10 mL) was added DPPA (1.36 g, 4.94 mmol, 1.07 mL, 1.5 eq) and Et3N (667 mg, 6.59 mmol, 917.67 µL, 2.0 eq) at rt. The resulting reaction mixture was heated to 80 °C and stirred for 1 hr, then cooled to rt. Next, the mixture was added. N-(1',2-dihydroxy-[1,2'-binaphthyl]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (1.09 g, 2.31 mmol, 0.7 eq) was added and the resulting reaction mixture was stirred at rt for 12 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 0:1 to 1:1) to give the product. The product was purified by reverse phase column chromatography (ACN:H2O = 0:1-1:1) to give a mixture of three regioisomers of the title compound as a solid (4.8 g, 33% yield) and used in the next step. For C 41 H 45 N3O 10 LCMS calculated for S: m / z = 771; found: m / z = 794 (M+Na).

[0143] Step 2: (2 S )-2-amino-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)butyric acid hydrochloride.

[0144] To a solution of tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)butanoate (4.8 g, 6.22 mmol, 1.0 eq) in DCM (50 mL) was added TFA (14.18 g, 124.37 mmol, 9.21 mL, 20 eq) at rt. The resulting mixture was stirred at rt for 12 hr. The mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse phase HPLC (Phenomenex Luna C18 column (250×70mm×15 µm); mobile phase: [water (0.04% HCl)-ACN]; B%: 25%-30%, 20 min) to obtain three isomers. These isomers were randomly named as compounds 6A, 6B, and 6C. Isomer 6A: 600 mg, solid. 1H NMR (400MHz, 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); for C 32 H 29 LCMS calculated for N3O8S: m / z = 615; found: 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); for C 32 H 29 LCMS calculated for N3O8S: m / z = 615; found: m / z = 616 (M+H). Isomer 6C: 850 mgs, solid. 1 H 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 (2, J = 8.8, 2H), 6.75 (s, 1H), 3.89 (m, 1H), 3.69 (s, 3H), 3.18 (m,2H), 1.90 (m, 2H); for C 32 H 29 LCMS calculated for N3O8S: m / z = 615; found: m / z = 616 (M+H).

[0145] N-((6)-6-hydroxy-6-oxido[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'-binaphthyl]-1'-yl dihydrogen phosphate (Compound 9).

[0146]

[0147] Step 1: N -((6)-6-Hydroxy-6-oxodinaphtho[1,2-d:1',2'-f][1,3,2]dioxaphosphine-15-yl)-4-methoxybenzenesulfonamide.

[0148] At 0°C, N To a solution of -(1',2-dihydroxy-[1,2'-binaphthyl]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (3.0 g, 6.36 mmol, 1.0 eq) in pyridine (30 mL) was added POCl3 (975 mg, 6.36 mmol, 591 µL, 1.0 eq). The resulting reaction mixture was stirred at 0 °C for 2 hr. The reaction was poured into ice water and the pH was adjusted to pH = 8 with 1N NaOH. The solution was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative reverse phase HPLC (Phenomenex Gemini-NX C18 75×30mm×3µm column; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain the product as a solid. The solid was added to EtOH / acetone (324 mL, 1:5). The resulting slurry was heated to 50 ° C for 30 min, during which the solid dissolved to obtain a clear solution. The solution was then cooled to 0 ° C and stirred for 2 hr, during which a precipitate formed. The resulting suspension was filtered and the solid was collected. The solid was then dried under high vacuum to obtain the title compound (578 mg, yield 19%) as a solid. 1 H NMR: (400MHz, Methanol-d4) δ = 10.16 (s, br, 1H), 8.27(d, 1H), 8.19 (d, 1H), 8.01 (dd, 2H), 7.74 (d, 2H), 7.59 (m, 3H), 7.50 (m,1H), 7.34-7.24 (m, 4H), 7.16 (s, br, 1H), 7.08 (d, 2H), 3.81 (s, 3H); for C 27H 20 LCMS calculated for NO7PS: m / z = 533; found: m / z = 532 (MH).

[0149] Step 2: 2-Hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl dihydrogen phosphate.

[0150] Will N A solution of -((6)-6-hydroxy-6-oxodinaphtho[1,2-d:1',2'-f][1,3,2]dioxaphosphopane-15-yl)-4-methoxybenzenesulfonamide (2 g, 3.75 mmol, 1.0 eq) in NaOH (1 M, 11.25 mL, 3.0 eq) was heated to 80°C for 3 hr with stirring. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (Welch XtimateC18 250×70mm×10µm column; mobile phase: [H2O (10mM 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 for 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 hr, during which a precipitate formed. The resulting suspension was filtered to collect the solid. The solid was then dried under high vacuum to obtain the title compound (160 mg, yield 22%) as a solid. 1 H NMR: (400MHz, 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). For C 27 H 22 LCMS calculated for NO8PS: m / z = 551, found: m / z = 552 (M+H).

[0151] 2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl (((R)-pyrrolidin-2-yl)methyl)carbamate (Compounds 15A and 15B).

[0152]

[0153] Step 1: (2R)-tert-butyl 2-(((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)methyl)pyrrolidine-1-carboxylate.

[0154] rt, to ( R To a solution of 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (3.8 g, 16.57 mmol, 1.0 eq) in toluene (40 mL) was added Et3N (3.35 g, 33.15 mmol, 4.61 mL, 2.0 eq) and DPPA (6.84 g, 24.86 mmol, 5.39 mL, 1.5 eq). The resulting reaction mixture was heated at 80°C and stirred for 1 hr. The reaction mixture was cooled to rt and then added N -(1',2-dihydroxy-[1,2'-binaphthyl]-4'-yl)-4-methoxybenzenesulfonamide (TTI-101) (7.82 g, 16.57 mmol, 1.0 eq) in toluene (40 mL). The resulting reaction mixture was stirred at rt for 2 hr. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase HPLC (Phenomenex LunaC18 column (250×70 mm×15 µm); mobile phase: [water (0.04% HCl)-ACN]; B%: 20%-80%, 20 min) to obtain a mixture of two regioisomers of the title compound as a solid (4.8 g, yield 42%). For C 38 H 39 LCMS calculated for N3O8S: m / z = 697; found: m / z = 720 (M+Na).

[0155] Step 2: 2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl (((R)-pyrrolidin-2-yl)methyl)carbamate hydrochloride.

[0156] rt, to (2 RTo a solution of tert-butyl 2-(((((2-hydroxy-4'-((4-methoxyphenyl)sulfonamido)-[1,2'-binaphthyl]-1'-yl)oxy)carbonyl)amino)methyl)pyrrolidine-1-carboxylate (4.8 g, 6.88 mmol, 1.0 eq) in DCM (50 mL) was added TFA (15.69 g, 137.58 mmol, 10.19 mL, 20 eq). The resulting reaction mixture was stirred at rt for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (Phenomenex Luna C18 (250×70 mm×15 μm column); mobile phase: [H2O(0.04%HCl)-ACN]; B%: 16%-46%, 20 min) to give the title compound as two isomers, which were randomly named Compounds 15A and 15B. Isomer 15A was then triturated with acetone:ACN (30 mL, 1:1) and the resulting solid was isolated by filtration and dried under high vacuum to afford 1.2 g of material 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); for C 33 H 31 LCMS calculated for N3O6S: m / z = 597; found: m / z = 598 (M+H). Isomer 15B was then added to acetone:EtOAc (20 mL, 1:1). The resulting slurry was stirred and heated to 50 °C for 30 min, during which time the solid completely dissolved to form a solution. The solution was then cooled to 0 °C and stirred for 2 hr, during which time a precipitate formed. The resulting suspension was filtered to collect the solid. The solid was then dried under high vacuum to give 400 mg of the material as a solid. 1H 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). 33 H 31 LCMS calculated for N3O6S: m / z = 597; found: m / z = 598 (M+H).

[0157] Attempts were made to synthesize the following compounds, but they could not be isolated due to their instability:

[0158] .

[0159] Example 2. Solubility, human plasma stability and solution stability of compounds The compounds were evaluated for solubility, plasma stability, and solution stability (Table 1).

[0160] Table 1. Solubility, plasma stability and solution stability of compounds of Formula I.

[0161]

[0162] Solution stability For compound 3, compound 4, compound 6A, compound 6B, compound 6C, compound 15A, compound 15B: For each compound, 10 μL of 10 mM DMSO stock solution was added to 490 μL DMSO to obtain a 200 μM working solution. Then 2 μL of the 200 μM working solution was added to the 96-well plate, corresponding to T0, T60, T120, T360, and T1440. Then 198 μL of 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) solution was added to the above corresponding wells except T0, so that the final test concentration at each time point (60, 120, 360, 1440 minutes) reached 2 μM. The final concentration of DMSO in the incubation mixture was 1%. The samples were incubated at 37°C, 600 rpm for the indicated time. After the incubation, the test samples at the corresponding time points (60, 120, 360, 1440 minutes) were removed and immediately mixed with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide & 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 tolbutamide & labetalol and 0.3% FA. When preparing T0 samples, 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide and labetalol and 0.3% FA was added, and then 198 μL of 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) was added to the corresponding wells. Then, 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide and labetalol and 0.3% FA. The sample was centrifuged at 4000 rpm and 4 °C for 20 min, and 60 μL of the supernatant was pipetted and mixed with 180 μL of pure water, and then mixed for LC / MS / MS analysis. The residual rate of the test compound in each incubation time was calculated based on the peak area ratio of analyte / IS: Remaining % (specified time)

[0163] PAR T : peak area ratio at a specified time; PAR0: peak area ratio at T0 incubation; and PAR: peak area ratio, the ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard For compound 9 and compound 9A: For each compound, 10 μL of 10 mM DMSO stock solution was added to 490 μL DMSO to obtain a 200 μM working solution. Then 2 μL of 200 μM working solution was added to a 96-well plate, corresponding to T0, T60, T120, T360, and T1440. Subsequently, 198 μL of 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) solution was added to the above corresponding wells except T0, so that the final test concentration at each time point (60, 120, 360, 1440 minutes) reached 2 μM. The final concentration of DMSO in the incubation mixture was 1%. Samples were incubated at 37°C, 600 rpm for the indicated time. After the incubation, the test samples at the corresponding time points (60, 120, 360, 1440 minutes) were removed and immediately mixed with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide & labetalol (internal standard). Then 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide & labetalol. When preparing the T0 sample, 198 μL of 75 mM phosphate buffer (pH 2.0, 3.5, 7.4) was transferred to the corresponding wells after adding 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide and labetalol. Then 200 μL of the resulting suspension was further diluted with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide and labetalol. The samples were centrifuged at 4000 rpm and 4°C for 20 min, and 60 μL of the supernatant was pipetted and mixed with 180 μL of pure water for LC / MS / MS analysis. The residual rate of the test compound at each incubation time was calculated based on the peak area ratio of the analyte / IS.

[0164] Solubility For each compound, 450 µL of 75 mM phosphate buffer (pH 2.0 and 7.4) was added to obtain a supersaturated suspension. The mixture was vortexed for at least 2 minutes. The sample was shaken at rt, 800 rpm for 24 hours and then centrifuged. The suspension was filtered through a PTFE filter medium. The filtrate was analyzed by HPLC (column: Waters XBridge C18 4.6*100 M; 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.

[0165] Plasma stability 98 μL / well of blank plasma was added to all 96-well reaction plates (blank, T0, T10, T30, T60, and T120). 2 μL / well of working solution of each compound (100 μM) was added to all reaction plates except the blank. All reaction plates containing the mixture of compound and plasma were incubated at 37°C in a water bath. At the end of the incubation, 400 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in ACN, optionally 0.1% FA) was added to precipitate proteins, vortexed and centrifuged. The supernatant was analyzed by LC-MS / MS.

[0166] Example 3. Pharmacokinetics of Compounds in Mice, Rats and Monkeys The pharmacokinetics of TTI-101 and the compound of Formula I were evaluated following a single intravenous (IV) injection of TTI-101 and oral (PO) gavage of the compound of Formula I in rats.

[0167] Twenty-four male SD rats were divided into four groups of 6 animals / group for four studies. Animals in Group 1 were administered TTI-101 via a single IV dose of 21.5 mg / kg. Animals in Groups 2, 3, and 4 were administered a single PO dose of Compound 3, Compound 4, and Compound 9, equivalent to 17.8, 18.1, and 19.2 mg / kg TTI-101 doses, respectively. Plasma samples were collected before (0), 0.083 hours (IV only), 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after dosing. The concentration of TTI-101 in plasma samples was determined by LC-MS / MS. The medium used for IV studies was DMSO / EtOH / PEG400 / saline (5 / 2 / 43 / 50 % v / v). The medium used for PO studies was 0.5% methylcellulose (400 cps) in 50 mM citrate buffer, pH~3.5 or PBS, pH~7.4.

[0168] Furthermore, TTI-101 administered orally in the form of a self-emulsifying drug dispersion (SEDD) (prepared as described in WO 2021 / 150912) exhibited F% = 40.4 in rats.

[0169] Table 2 shows exemplary PK data for compounds of Formula I in rats.

[0170] Table 2.

[0171] 1 The plasma concentration that can be measured at 24 hours, so AUC 最后 Up to 24 hours.

[0172] 2 The plasma concentration that can be measured at 8 hours, so AUC 最后 Up to 8 hours. F% may be underestimated.

[0173] MC = Methylcellulose PBS = Phosphate Buffered Saline ND = Not Determined F = bioavailability, calculated based on dose level The pharmacokinetics of TTI-101 and the compound of Formula I were evaluated in monkeys following a single intravenous (IV) or oral (PO) gavage of TTI-101 and the compound of Formula I.

[0174] This study was divided into 5 phases and used a group of 3 male cynomolgus monkeys. Animals in phase 1 were administered TTI-101 by a single intravenous injection at a dose of 26 mg / kg. Animals in phases 2, 3, 4, and 5 were administered TTI-101 SEDD, compound 3, compound 9A, and compound 9 by a single oral administration, respectively. Plasma samples were collected before (0), after dosing (phase 1, phase 2, phase 3, phase 4, and phase 5) 0.083 (phase 1 only), 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (except phase 1). The concentration of TTI-101 in plasma samples was determined by LC-MS / MS. The SEDD formulation of TTI-101 was prepared according to the method described in WO 2021 / 150912.

[0175] Table 3 shows exemplary PK data for compounds of Formula I in monkeys.

[0176] Table 3.

[0177] 1 The plasma concentration that can be measured at 24 hours, so AUC 最后 Up to 24 hours.

[0178] 2 The plasma concentration that can be measured at 8 hours, so AUC 最后 Up to 8 hours. F% may be underestimated.

[0179] MC=Methylcellulose PBS = Phosphate buffered saline ND = Not Determined F = bioavailability, calculated based on dose level H22 (HCC model) syngeneic mice were treated orally twice a day with Compound 9 (eg, 34, 69, and 103 mg / kg in PBS, equivalent to 25, 50, and 75 mg / kg of TTI-101, respectively) and TTI-101 SEDD (eg, 50 mg / kg). Figure 1 Exposure curves for Compound 9 and TTI-101 SEDD are shown. Figure 1 It was shown that compound 9 had more than three times the exposure in mice compared to TTI-101 SEDD at day 21.

Claims

1. A compound of formula I, (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Haloalkoxy; R 1 , R 2 and R 3 Each independently is H, C(=O)NR A R B 、P(=O)(OH)(R C ) or C 1-4 Alkylene-OP(=O)(OH)(R C );or R 1 and R 2 Together they form: ; The premise is R 1 , R 2 and R 3 Not at the same time H; R A Is H or C 1-4 alkyl; R B It is C 1-6 Alkylene-N(H)(C 1-6 Alkyl), C 1-6 Alkylene-(5-8 membered heterocyclic group), C 1-6 Alkylene-C(=O)OH, optionally amine, C 1-4 Alkyl or benzyl substitution; R C It is C 1-4 alkyl or hydroxyl; and n is an integer 0, 1, 2 or 3.

2. The compound according to claim 1, wherein R 3 It's H.

3. The compound according to claim 1, wherein R 3 It is C(=O)NR A R B .

4. A compound according to any one of claims 1 to 3, wherein R 1 It's H.

5. The compound according to any one of claims 1 to 3, wherein R 1 and R 2 Together they form: .

6. A compound according to any one of claims 1 to 4, wherein R 2 It is C(=O)NR A R B .

7. A compound according to any one of claims 1 to 4, wherein R 2 It is P(=O)(OH)(R C ).

8. A compound according to any one of claims 1 to 4, wherein R 2 It is C 1-4 Alkylene-OP(=O)(OH)(R C ).

9. The compound according to any one of claims 1 to 8, wherein n is 0 or 1.

10. The compound according to any one of claims 1 to 9, wherein n is 1.

11. The compound according to claim 1, wherein the compound is a compound of formula IA: (IA) or a pharmaceutically acceptable salt or solvate thereof.

12. The compound according to claim 11, wherein A is C 1-4 Alkoxy.

13. The compound according to claim 12, wherein the compound is a compound of formula IG: (IG) or a pharmaceutically acceptable salt or solvate thereof.

14. The compound according to claim 13, wherein the compound is a compound of formula IH or IK: (IH)or (IK) or a pharmaceutically acceptable salt or solvate thereof.

15. The compound according to claim 13, wherein the compound is a compound of formula II or a compound of formula IL: (II)or (IL) or a pharmaceutically acceptable salt or solvate thereof.

16. The compound according to claim 1, wherein the compound is a compound of formula IJ: (IJ) or a pharmaceutically acceptable salt or solvate thereof.

17. The compound according to claim 1, wherein the compound is: , , , , , , , , , , or , or a pharmaceutically acceptable salt or solvate thereof.

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

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer in a subject in need thereof.

20. The compound for use according to claim 19, 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 cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia or lymphoma.

21. The compound for use according to claim 19, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia or pancreatic cancer.

22. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating fibrosis in a subject in need thereof.

23. The compound for use according to claim 22, wherein the fibrosis is pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, renal fibrosis, myelofibrosis, dermal fibrosis or systemic sclerosis.

24. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating an inflammatory disease or disorder in a subject in need thereof.

25. The compound for use according to claim 24, wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis or asthma.

26. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disease or disorder in a subject in need thereof.

27. The compound for use according to claim 26, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy, diabetic neuropathy or familial amyloid polyneuropathy.

28. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating non-alcoholic fatty liver disease or steatohepatitis in a subject in need thereof.

29. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cachexia in a subject in need thereof.

30. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating an allergic reaction in a subject in need thereof.

31. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

32. The method of claim 31, 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 cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, or lymphoma.

33. The method of claim 31, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer.

34. A method of treating fibrosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

35. The method of claim 34, wherein the fibrosis is pulmonary fibrosis, bonemarrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, renal fibrosis, myelofibrosis, dermal fibrosis, or systemic sclerosis.

36. A method of treating an inflammatory disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

37. The method of claim 36, wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis, or asthma.

38. A method of treating a neurodegenerative disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

39. The method of claim 38, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy.

40. A method for treating non-alcoholic fatty liver disease or steatohepatitis in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

41. A method for treating cachexia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

42. A method for treating an allergic reaction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

Images