WO2024148041A1 - Stat3 degraders and uses thereof - Google Patents

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same to treat a STAT3-mediated disorder, disease, or condition in a patient. The present invention provides 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl compounds useful for the modulation of signal transducers and activators of transcription 3 ("STATS") via ubiquitination and/or degradation, e.g. STAT3 degraders and/or inhibitors, compositions thereof, and methods of using the same to treat a STAT3-mediated disorder, disease, or condition in a patient for the degradation of STAT3 to suppress STATS signaling for the treatment of cancer.

Description

STAT3 DEGRADERS AND USES THEREOF TECHNICAL FIELD OF THE INVENTION [0001] The present invention provides compounds and methods useful for the modulation of signal transducers and activators of transcription 3 (“STAT3”) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION [0002] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. [0003] The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors upon binding to their cognate cell surface receptors resulting in the recruitment and phosphorylation of STAT3 by Janus kinase (JAK), dimerization, nuclear translocation and transcriptional regulation of STAT3 target genes. While in normal cells STAT3 activity is tightly controlled by feedback regulation, in diseases including cancer and auto-immunity, STAT3 activity becomes deregulated by mechanisms that result in persistent activation of STAT3 as evidence by high levels of phosphorylated STAT3 (pSTAT3). Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of pSTAT3. Aberrant activation of STAT3 has been shown to occur through direct mutation of the STAT3 gene, activation of upstream kinases such as JAK or ALK by mutation or translocation, reduced expression of negative regulators such as SOC3 and elevated receptor signaling from overexpression of cytokine and growth factors in the tumor microenvironment. [0004] The mechanisms by which deregulated STAT3 contribute to tumor establishment and progression are multifactorial. Among the target genes regulated by STAT3 are key effectors of several hallmarks of cancer including proliferative signaling (CCND1, CCND2), resisting cell death (BCL2-L1, MCL-1), angiogenesis (VEGF, HIF1a), deregulated cellular energetics (MYC), avoiding immune destruction (PD- L1, IFNA) and tumor-promoting inflammation (IL-6). In cancer cell models with strong STAT3 activation such as anaplastic large cell lymphoma (ALCL), genetic knockdown of STAT3 is sufficient to inhibit proliferation and induce apoptosis confirming dependency on STAT3 signaling. In addition to these cancer cell autonomous pathways, activated STAT3 also promotes a suppressive TME through direct regulation of immune cell function and regulation of cancer cell-TME crosstalk. Activation of STAT3 in innate and adaptive immune cells generally favors expansion of immune suppressive cells while reducing the proliferation, maturation and function of cytolytic effector cells. Targeting STAT3 with antisense oligonucleotides that are preferentially taken up by myeloid cells has been shown to reverse immune suppression and restore anti-tumor activity of cytotoxic T cells in mouse syngeneic tumor models. Finally STAT3 has been shown to be activated in response to both chemo- and targeted therapies such as EGFR inhibitors and contributes to the development of drug-resistance. Collectively these data illustrate the importance of STAT3 signaling to tumor establishment and growth, to tumor-extrinsic immune suppression in the TME and to the development of resistance to standard therapies thereby suggesting that selective degradation of STAT3 may be an effective means to suppress STAT3 signaling for the treatment of cancer. [0005] A need exists to develop STAT3 degraders for use in cancer therapy. SUMMARY OF THE INVENTION [0006] In one aspect, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: each of A¹, A², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is as defined herein. [0007] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT3 protein. Such diseases, disorders, or conditions include those described herein. [0008] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information and procedures. DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Certain Aspects of the Invention [0009] The present invention provides compounds, compositions, and methods for treatment, prevention, and/or reduction of a risk of diseases, disorders, or conditions such as those mediated by STAT3 or a mutant thereof. In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein and described in embodiments. [0010] In one aspect, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

2. Definitions [0011] The term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit). [0012] As used herein, “Compound A” refers to STAT3 degrader (2-(((5S,8S,10aR)-3-acetyl-8-(((S)-5- amino-1-(2-chloro-3-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)- 5-oxopentan-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indole-5- carbonyl)phosphonic acid, of formula:

. Compound A or pharmaceutically acceptable salts thereof can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2020/206424, the entire contents of which is incorporated herein by reference. [0014] As used herein, “Gluc” refers to a glucuronide derivative, i.e.:

. [0015] As used herein, “OGluc” refers to a glucuronide ether derivative, i.e.:

. [0016] As used herein, “ManNAc” refers to an N-Acetylmannosamine derivative, i.e.:

. [0017] As used herein, “OManNAc” refers to an N-Acetylmannosamine ether derivative, i.e.:

. [0013] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. [0014] The term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like). In some embodiments, the patient is a human. [0015] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0016] “Therapeutically effective amount” includes an amount of a compound of the invention that is effective when administered alone or in combination to treat the desired condition or disorder. “Therapeutically effective amount” includes an amount of a combination of compounds claimed that is effective to treat the desired condition or disorder. The combination of compounds can be additive and is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul.1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower incidence of adverse side effects and/or toxicity, increased efficacy, or some other beneficial effect of the combination compared with the individual components. [0017] As used herein, the term “about” refers to within 20% of a given value. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value. [0018] As used herein, the term “provided compound” refers to any genus, subgenus, and/or species set forth herein. [0019] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. [0020] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [0021] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. [0022] As used herein, the term “inhibitor” is defined as a compound that binds to and /or inhibits STAT3 with measurable affinity. In certain embodiments, an inhibitor has an IC₅₀ and/or binding constant of less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0023] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and /or inhibits both STAT3 and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of STAT3. In certain embodiments, a degrader has an DC50 of less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0024] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in STAT3 activity between a sample comprising a compound of the present invention, or composition thereof, and STAT3, and an equivalent sample comprising STAT3, in the absence of said compound, or composition thereof. 3. Description of Exemplary Compounds Formula I [0025] According to one aspect, the present invention provides a compound of formula I:

R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc; provided that when

least A² is =O, OGluc, or OManNAc or at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OH, OGluc, or OManNAc. [0026] As defined above and described herein,

. [0027] In some embodiments, A¹ is H. In some embodiments, A¹ is

. [0028] As defined above and described herein, A² is =O or OB¹. [0029] In some embodiments, A² is =O. In some embodiments, A² is OB¹. [0030] As defined above and described herein, B¹ is H, Gluc, or ManNAc. [0031] In some embodiments, B¹ is H. In some embodiments, B¹ is Gluc. In some embodiments, B¹ is ManNAc. [0032] As defined above and described herein, each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc. [0033] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OH. [0034] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹,

[0035] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is OH. [0036] In some embodiments, one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is OH. [0037] In some embodiments, one of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is OH. [0038] In some embodiments, one of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, and R⁶¹ is OH. [0039] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OGluc. [0040] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹,

[0041] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is OGluc. [0042] In some embodiments, one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is OGluc. [0043] In some embodiments, one of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is OGluc. [0044] In some embodiments, one of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, and R⁶¹ is OGluc. [0045] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OManNAc. [0046] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹,

[0047] In some embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is OManNAc. [0048] In some embodiments, one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is OManNAc. [0049] In some embodiments, one of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is OManNAc. [0050] In some embodiments, one of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, and R⁶¹ is OManNAc. [0051] In some embodiments, R¹ is H. In some embodiments, R² is H. In some embodiments, R³ is H. In some embodiments, R⁴ is H. In some embodiments, R⁵ is H. In some embodiments, R⁶ is H. In some embodiments, R⁷ is H. In some embodiments, R⁸ is H. In some embodiments, R⁹ is H. In some embodiments, R¹⁰ is H. In some embodiments, R¹¹ is H. In some embodiments, R¹² is H. In some embodiments, R¹³ is H. In some embodiments, R¹⁴ is H. In some embodiments, R¹⁵ is H. In some embodiments, R¹⁶ is H. In some embodiments, R¹⁷ is H. In some embodiments, R¹⁸ is H. In some embodiments, R¹⁹ is H. In some embodiments, R²⁰ is H. In some embodiments, R²¹ is H. In some embodiments, R²² is H. In some embodiments, R²³ is H. In some embodiments, R²⁴ is H. In some embodiments, R²⁵ is H. In some embodiments, R²⁶ is H. In some embodiments, R²⁷ is H. In some embodiments, R²⁸ is H. In some embodiments, R²⁹ is H. In some embodiments, R³⁰ is H. In some embodiments, R³¹ is H. In some embodiments, R³² is H. In some embodiments, R³³ is H. In some embodiments, R³⁴ is H. In some embodiments, R³⁵ is H. In some embodiments, R³⁶ is H. In some embodiments, R³⁷ is H. In some embodiments, R³⁸ is H. In some embodiments, R³⁹ is H. In some embodiments, R⁴⁰ is H. In some embodiments, R⁴¹ is H. In some embodiments, R⁴² is H. In some embodiments, R⁴³ is H. In some embodiments, R⁴⁴ is H. In some embodiments, R⁴⁵ is H. In some embodiments, R⁴⁶ is H. In some embodiments, R⁴⁷ is H. In some embodiments, R⁴⁸ is H. In some embodiments, R⁴⁹ is H. In some embodiments, R⁵⁰ is H. In some embodiments, R⁵¹ is H. In some embodiments, R⁵² is H. In some embodiments, R⁵³ is H. In some embodiments, R⁵⁴ is H. In some embodiments, R⁵⁵ is H. In some embodiments, R⁵⁶ is H. In some embodiments, R⁵⁷ is H. In some embodiments, R⁵⁸ is H. In some embodiments, R⁵⁹ is H. In some embodiments, R⁶⁰ is H. In some embodiments, R⁶¹ is H. In some embodiments, R⁶² is H. In some embodiments, R⁶³ is H. In some embodiments, R⁶⁴ is H. [0052] In some embodiments, R¹ is OH. In some embodiments, R² is OH. In some embodiments, R³ is OH. In some embodiments, R⁴ is OH. In some embodiments, R⁵ is OH. In some embodiments, R⁶ is OH. In some embodiments, R⁷ is OH. In some embodiments, R⁸ is OH. In some embodiments, R⁹ is OH. In some embodiments, R¹⁰ is OH. In some embodiments, R¹¹ is OH. In some embodiments, R¹² is OH. In some embodiments, R¹³ is OH. In some embodiments, R¹⁴ is OH. In some embodiments, R¹⁵ is OH. In some embodiments, R¹⁶ is OH. In some embodiments, R¹⁷ is OH. In some embodiments, R¹⁸ is OH. In some embodiments, R¹⁹ is OH. In some embodiments, R²⁰ is OH. In some embodiments, R²¹ is OH. In some embodiments, R²² is OH. In some embodiments, R²³ is OH. In some embodiments, R²⁴ is OH. In some embodiments, R²⁵ is OH. In some embodiments, R²⁶ is OH. In some embodiments, R²⁷ is OH. In some embodiments, R²⁸ is OH. In some embodiments, R²⁹ is OH. In some embodiments, R³⁰ is OH. In some embodiments, R³¹ is OH. In some embodiments, R³² is OH. In some embodiments, R³³ is OH. In some embodiments, R³⁴ is OH. In some embodiments, R³⁵ is OH. In some embodiments, R³⁶ is OH. In some embodiments, R³⁷ is OH. In some embodiments, R³⁸ is OH. In some embodiments, R³⁹ is OH. In some embodiments, R⁴⁰ is OH. In some embodiments, R⁴¹ is OH. In some embodiments, R⁴² is OH. In some embodiments, R⁴³ is OH. In some embodiments, R⁴⁴ is OH. In some embodiments, R⁴⁵ is OH. In some embodiments, R⁴⁶ is OH. In some embodiments, R⁴⁷ is OH. In some embodiments, R⁴⁸ is OH. In some embodiments, R⁴⁹ is OH. In some embodiments, R⁵⁰ is OH. In some embodiments, R⁵¹ is OH. In some embodiments, R⁵² is OH. In some embodiments, R⁵³ is OH. In some embodiments, R⁵⁴ is OH. In some embodiments, R⁵⁵ is OH. In some embodiments, R⁵⁶ is OH. In some embodiments, R⁵⁷ is OH. In some embodiments, R⁵⁸ is OH. In some embodiments, R⁵⁹ is OH. In some embodiments, R⁶⁰ is OH. In some embodiments, R⁶¹ is OH. In some embodiments, R⁶² is OH. In some embodiments, R⁶³ is OH. In some embodiments, R⁶⁴ is OH. [0053] In some embodiments, R¹ is OGluc. In some embodiments, R² is OGluc. In some embodiments, R³ is OGluc. In some embodiments, R⁴ is OGluc. In some embodiments, R⁵ is OGluc. In some embodiments, R⁶ is OGluc. In some embodiments, R⁷ is OGluc. In some embodiments, R⁸ is OGluc. In some embodiments, R⁹ is OGluc. In some embodiments, R¹⁰ is OGluc. In some embodiments, R¹¹ is OGluc. In some embodiments, R¹² is OGluc. In some embodiments, R¹³ is OGluc. In some embodiments, R¹⁴ is OGluc. In some embodiments, R¹⁵ is OGluc. In some embodiments, R¹⁶ is OGluc. In some embodiments, R¹⁷ is OGluc. In some embodiments, R¹⁸ is OGluc. In some embodiments, R¹⁹ is OGluc. In some embodiments, R²⁰ is OGluc. In some embodiments, R²¹ is OGluc. In some embodiments, R²² is OGluc. In some embodiments, R²³ is OGluc. In some embodiments, R²⁴ is OGluc. In some embodiments, R²⁵ is OGluc. In some embodiments, R²⁶ is OGluc. In some embodiments, R²⁷ is OGluc. In some embodiments, R²⁸ is OGluc. In some embodiments, R²⁹ is OGluc. In some embodiments, R³⁰ is OGluc. In some embodiments, R³¹ is OGluc. In some embodiments, R³² is OGluc. In some embodiments, R³³ is OGluc. In some embodiments, R³⁴ is OGluc. In some embodiments, R³⁵ is OGluc. In some embodiments, R³⁶ is OGluc. In some embodiments, R³⁷ is OGluc. In some embodiments, R³⁸ is OGluc. In some embodiments, R³⁹ is OGluc. In some embodiments, R⁴⁰ is OGluc. In some embodiments, R⁴¹ is OGluc. In some embodiments, R⁴² is OGluc. In some embodiments, R⁴³ is OGluc. In some embodiments, R⁴⁴ is OGluc. In some embodiments, R⁴⁵ is OGluc. In some embodiments, R⁴⁶ is OGluc. In some embodiments, R⁴⁷ is OGluc. In some embodiments, R⁴⁸ is OGluc. In some embodiments, R⁴⁹ is OGluc. In some embodiments, R⁵⁰ is OGluc. In some embodiments, R⁵¹ is OGluc. In some embodiments, R⁵² is OGluc. In some embodiments, R⁵³ is OGluc. In some embodiments, R⁵⁴ is OGluc. In some embodiments, R⁵⁵ is OGluc. In some embodiments, R⁵⁶ is OGluc. In some embodiments, R⁵⁷ is OGluc. In some embodiments, R⁵⁸ is OGluc. In some embodiments, R⁵⁹ is OGluc. In some embodiments, R⁶⁰ is OGluc. In some embodiments, R⁶¹ is OGluc. In some embodiments, R⁶² is OGluc. In some embodiments, R⁶³ is OGluc. In some embodiments, R⁶⁴ is OGluc. [0054] In some embodiments, R¹ is OManNAc. In some embodiments, R² is OManNAc. In some embodiments, R³ is OManNAc. In some embodiments, R⁴ is OManNAc. In some embodiments, R⁵ is OManNAc. In some embodiments, R⁶ is OManNAc. In some embodiments, R⁷ is OManNAc. In some embodiments, R⁸ is OManNAc. In some embodiments, R⁹ is OManNAc. In some embodiments, R¹⁰ is OManNAc. In some embodiments, R¹¹ is OManNAc. In some embodiments, R¹² is OManNAc. In some embodiments, R¹³ is OManNAc. In some embodiments, R¹⁴ is OManNAc. In some embodiments, R¹⁵ is OManNAc. In some embodiments, R¹⁶ is OManNAc. In some embodiments, R¹⁷ is OManNAc. In some embodiments, R¹⁸ is OManNAc. In some embodiments, R¹⁹ is OManNAc. In some embodiments, R²⁰ is OManNAc. In some embodiments, R²¹ is OManNAc. In some embodiments, R²² is OManNAc. In some embodiments, R²³ is OManNAc. In some embodiments, R²⁴ is OManNAc. In some embodiments, R²⁵ is OManNAc. In some embodiments, R²⁶ is OManNAc. In some embodiments, R²⁷ is OManNAc. In some embodiments, R²⁸ is OManNAc. In some embodiments, R²⁹ is OManNAc. In some embodiments, R³⁰ is OManNAc. In some embodiments, R³¹ is OManNAc. In some embodiments, R³² is OManNAc. In some embodiments, R³³ is OManNAc. In some embodiments, R³⁴ is OManNAc. In some embodiments, R³⁵ is OManNAc. In some embodiments, R³⁶ is OManNAc. In some embodiments, R³⁷ is OManNAc. In some embodiments, R³⁸ is OManNAc. In some embodiments, R³⁹ is OManNAc. In some embodiments, R⁴⁰ is OManNAc. In some embodiments, R⁴¹ is OManNAc. In some embodiments, R⁴² is OManNAc. In some embodiments, R⁴³ is OManNAc. In some embodiments, R⁴⁴ is OManNAc. In some embodiments, R⁴⁵ is OManNAc. In some embodiments, R⁴⁶ is OManNAc. In some embodiments, R⁴⁷ is OManNAc. In some embodiments, R⁴⁸ is OManNAc. In some embodiments, R⁴⁹ is OManNAc. In some embodiments, R⁵⁰ is OManNAc. In some embodiments, R⁵¹ is OManNAc. In some embodiments, R⁵² is OManNAc. In some embodiments, R⁵³ is OManNAc. In some embodiments, R⁵⁴ is OManNAc. In some embodiments, R⁵⁵ is OManNAc. In some embodiments, R⁵⁶ is OManNAc. In some embodiments, R⁵⁷ is OManNAc. In some embodiments, R⁵⁸ is OManNAc. In some embodiments, R⁵⁹ is OManNAc. In some embodiments, R⁶⁰ is OManNAc. In some embodiments, R⁶¹ is OManNAc. In some embodiments, R⁶² is OManNAc. In some embodiments, R⁶³ is OManNAc. In some embodiments, R⁶⁴ is OManNAc. [0055] In some embodiments, one OH is present in the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the OH present in the compound of formula I or a pharmaceutically acceptable salt thereof is present as an N-oxide. In some embodiments, one Gluc is present in the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, one OGluc is present in the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, one ManNAc is present in the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, one OManNAc is present in the compound of formula I or a pharmaceutically acceptable salt thereof. [0056] Non-limiting examples of R¹-R⁶⁴ combinations for formula I are shown in Table 1A below where

The six parts of the Table, taken together, show examples of R¹-R⁶⁴ combinations. Table 1A-Part 1: Exemplary formula I substituent combinations.

Table 1A-Part 2: Exemplary formula I substituent combinations.

Table 1A-Part 3: Exemplary formula I substituent combinations.

Table 1A-Part 4: Exemplary formula I substituent combinations.

Table 1A-Part 5: Exemplary formula I substituent combinations.

Table 1A-Part 6: Exemplary formula I substituent combinations.

[0057] Non-limiting examples of R¹-R⁶⁴ combinations for formula I are shown in Table 1B below where

The six parts of the Table, taken together, show examples of R¹-R⁶⁴ combinations. In Table 1B below, OG = OGluc. Table 1B-Part 1: Exemplary formula I substituent combinations.

Table 1A-Part 2: Exemplary formula I substituent combinations.

Table 1B-Part 3: Exemplary formula I substituent combinations.

Table 1B-Part 4: Exemplary formula I substituent combinations.

[0058] Table 1B-Part 5: Exemplary formula I substituent combinations.

Table 1B-Part 6: Exemplary formula I substituent combinations.

[0059] Non-limiting examples of R¹-R⁶⁴ combinations for formula I are shown in Table 1C below where

The six parts of the Table, taken together, show examples of R¹-R⁶⁴ combinations. In Table 1C below, OM = OManNAc. Table 1C-Part 1: Exemplary formula I substituent combinations.

Table 1C-Part 2: Exemplary formula I substituent combinations.

Table 1C-Part 3: Exemplary formula I substituent combinations.

Table 1C-Part 4: Exemplary formula I substituent combinations.

Table 1C-Part 5: Exemplary formula I substituent combinations.

Table 1C-Part 6: Exemplary formula I substituent combinations.

[0060] According to another aspect, the present invention provides a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴,

independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³²,

, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OH, OGluc, or OManNAc. [0061] According to another aspect, the present invention provides a compound of formula I-b:

I-b or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,

, R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁶², R⁶³, and R⁶⁴ is OH, OGluc, or OManNAc. [0062] According to another aspect, the present invention provides a compound of formula I-c:

I-c or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is OH, OGluc, or OManNAc. [0063] According to another aspect, the present invention provides a compound of formula I-d:

I-d or a pharmaceutically acceptable salt thereof, wherein: each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc. [0064] According to another aspect, the present invention provides a compound of formula I-e:

I-e or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is independently H, OH, OGluc, or OManNAc. [0065] According to another aspect, the present invention provides a compound of formula I-f:

or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is OH, OGluc, or OManNAc. [0066] According to another aspect, the present invention provides a compound of formula I-g:

or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is OH, OGluc, or OManNAc. [0067] According to another aspect, the present invention provides a compound of formula I-h:

or a pharmaceutically acceptable salt thereof, wherein: B¹ is H, Gluc, or ManNAc; and each of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, and R⁶¹ is independently H, OH, OGluc, or OManNAc; provided that at least B¹ is Gluc or ManNAc or at least one of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸,

OGluc, or OManNAc. [0068] According to another aspect, the present invention provides a compound of formula I-i:

or a pharmaceutically acceptable salt thereof, wherein: A² is =O or OB¹; and B¹ is H, Gluc, or ManNAc. [0069] In some embodiments, the compound of formula I is: , , ,

,

, , ,

,

, , ,

,

,

, or a pharmaceutically acceptable salt thereof. [0070] In some embodiments, a compound of formula I is a metabolite of Compound A. In some embodiments, the metabolite is formed upon exposure of Compound A to a human, mouse, rat, monkey (e.g., cynomolgus monkey), or dog (e.g., beagle). In some embodiments, the metabolite is formed by hepatocytes. In some embodiments, the metabolite is formed during first-pass metabolism. 4. Pharmaceutically acceptable compositions [0071] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably degrade and/or inhibit STAT3 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably degrade and/or inhibit STAT3 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [0072] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [0073] Inhibition and/or degradation of STAT3 protein or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays. [0074] The term “patient” as used herein, means an animal, preferably a mammal, and most preferably a human. [0075] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention 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 silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0076] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory or degradatory active metabolite or residue thereof. [0077] As used herein, the term “inhibitory active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of STAT3 protein, or a mutant thereof. [0078] As used herein, the term “degradatory active metabolite or residue thereof” means that a metabolite or residue thereof is also a degrader of STAT3 protein, or a mutant thereof. [0079] In certain embodiments, a provided compound is administered as a prodrug. [0080] The term “prodrug” refers to a compound that is made more active in vivo. A provided compound can also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the provided compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as a phosphonate ester (the “prodrug”), but then is metabolically hydrolyzed to the phosphonic acid or a conjugate base thereof, the active entity. Additional examples include peptidyl derivatives of a compound. The term “therapeutically acceptable prodrug,” refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. [0081] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0082] For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [0083] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [0084] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [0085] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [0086] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [0087] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [0088] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [0089] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [0090] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [0091] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions. [0092] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. 5. Uses of Compounds and Pharmaceutically Acceptable Compositions [0093] Compounds and compositions described herein are generally useful for the degradation and/or inhibition of STAT3 protein activity. [0094] The activity of a compound utilized in this invention as a degrader and/or inhibitor of STAT3 or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the activity and/or the subsequent functional consequences of activated STAT protein, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to a STAT3 protein. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/STAT3 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with a STAT3 protein bound to known radioligands. Representative in vitro and in vivo assays useful in assaying a STAT3 inhibitor include those described and disclosed in, e.g., Schust et al., “A high- throughput fluorescence polarization assay for signal transducer and activator of transcription 3” Anal. Biochem.2004, 333(1):114; Müller et al., “A high-throughput assay for signal transducer and activator of transcription 5b based on fluorescence polarization” Anal. Biochem.2008, 375(2):249. Detailed conditions for assaying a compound utilized in this invention as a degrader and/or inhibitor of STAT3 protein, or a mutant thereof, are set forth in the Examples below. [0095] The STAT family of proteins are cytoplasmic transcription factors with important roles in mediating responses to cytokines and growth factors, including promoting cell growth and differentiation, and inflammation and immune responses (Bromberg et al., Breast Cancer Res.2000, 2:86-90; Darnell et al., Nat. Rev. Cancer 2002, 2:740-749). STAT proteins are classically activated by tyrosine (Tyr) kinases, such as Janus kinases (JAKs) and Src family kinases, in response to the binding of cytokine and growth factors to their cognate receptors (Darnell et al., Science 1994, 264:1415). The Tyr phosphorylation (pTyr) promotes dimerization between two activated STAT:STAT monomers through a reciprocal pTyr- Src homology SH2 domain interactions. Active STAT:STAT dimers translocate to the nucleus to induce gene transcription by binding to specific DNA-response elements in the promoters of target genes to regulate gene expression. By contrast, aberrantly-active STAT3, one of the STAT family members, has been implicated in many human tumors and represents an attractive target for drug discovery. Persistently activated STAT3 and, to some extent, STAT5 increase tumor cell proliferation, survival and invasion while suppressing anti-tumor immunity. The persistent activation of STAT3 also mediates tumor- promoting inflammation. This aberrant activation of STAT3 occurs in glioma, breast, prostate, ovarian, and many other human cancers, whereby it promotes malignant progression (Yu & Jove, Nat. Rev. Cancer 2004, 4:97-105). JAKs, Src, and epidermal growth factor receptor (EGFR) are STAT3 upstream regulators (Bromberg et al., Mol. Cell. Biol.1998, 18:2553; Sartor et al., Cancer Res.1997, 57:978; Garcia et al., Oncogene 2001, 20:2499). Mechanisms by which constitutively-active STAT3 mediates tumorigenesis include dysregulation of gene expression that leads to uncontrolled growth and survival of tumor cells, enhanced tumor angiogenesis, and metastasis and the suppression of tumor immune surveillance (Yu & Jove 2004; Bromberg & Darnell, Oncogene 2000, 19:2468-2473; Bowman et al., Oncogene 2000, 19:2474-2488; Turkson & Jove, Oncogene 2000, 19:6613-6626; Turkson, Expert Opin. Ther. Targets 2004, 8:409-422; Wang et al., Nat. Med.2004, 10:48-54). [0096] The main domains of STAT3 protein include the tetramerization and leucine zipper at the N- terminus, the DNA binding domain, and the SH2 transactivation domain at the carboxy-terminal end. The SH2 region is responsible for the binding of STAT3 to the tyrosine-phosphorylated receptors and for the dimerization which is necessary for DNA binding and gene expression (Zhong et al., Science 1994, 264:95). STAT3 is activated by phosphorylation at Y-705, which leads to dimer formation, nuclear translocation, recognition of STAT3-specific DNA binding elements, and activation of target gene transcription (Darnell 1994; Zhong 1994). [0097] The constitutive activation of STAT3 is frequently detected in breast carcinoma cell lines but not in normal breast epithelial cells (Garcia et al., Cell. Growth. Differ.1997, 8:1267; Bowman 2000). It has been reported that approximately 60 percent of breast tumors contain persistently activated STAT3 (Dechow et al., Proc. Natl. Acad. Sci. USA 2004, 101:10602). STAT3 has been classified as a proto- oncogene because activated STAT3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice (Bromberg et al., Cell 1999, 98:295). STAT3 may participate in oncogenesis by stimulating cell proliferation, promoting angiogenesis, and conferring resistance to apoptosis induced by conventional therapies (Catlett-Falcone et al., Curr. Opin. Oncol.1999, 11:1; Catlett-Falcone et al., Immunity 1999, 10:105; Alas et al., Clin. Cancer Res.2003, 9:316; Wei et al., Oncogene 2003, 22:1517). Possible downstream targets through which STAT3 promotes oncogenesis include up- regulation of anti-apoptotic factors (Bcl-2, survivin, Mcl-1, and Bcl-X_L), cell-cycle regulators (cyclin D1, MEK5, and c-myc), and inducer of tumor angiogenesis (VEGF) (Bromberg et al., Cell 1999, 98:295; Wei et al., Oncogene 2003, 22:1517; Real et al., Oncogene 2002, 21:7611; Puthier et al., Eur. J. Immunol.1999, 29:3945; Niu et al., Oncogene 2002, 21:2000; Kiuchi et al., J. Exp. Med.1999, 189:63; Song et al., Oncogene 2004, 23:8301). Activated STAT3 signaling directly contributes to malignant progression of cancer. STAT3 oncogenic function acts through the pro-survival proteins such as survivin, Mcl-1, Bcl-2, and Bcl-X_L and results in the prevention of apoptosis (Real et al., Oncogene 2002, 21:7611; Aoki et al., Blood 2003, 101:1535; Epling-Burnette et al., J. Clin. Invest.2001, 107:351; Nielsen et al., Leukemia 1999, 13:735). Blockade of STAT3 signaling inhibits cancer cell growth, demonstrating that STAT3 is essential to the survival or growth of tumor cells (Alas et al., Clin. Cancer Res.2003, 9:316; Aoki et al., Blood 2003, 101:1535; Epling-Burnette et al., J. Clin. Invest.2001, 107:351; Burke et al., Oncogene 2001, 20:7925; Mora et al., Cancer Res.2002, 62:6659; Ni et al., Cancer Res.2000, 60:1225; Rahaman et al., Oncogene 2002, 21:8404). [0098] Recent evidence also reveals the role of STAT3 in modulating mitochondrial functions and STAT3 crosstalk with other proteins, such as NF-κB, that promotes the malignant phenotype. Many human tumors harbor aberrantly-active STAT3 signaling, and studies in experimental models indicate tumor cells and tumors harboring constitutively-active STAT3 are responsive to STAT3 signaling modulators (Gough et al., Science 2009, 324:1713; Yu et al., Nat. Rev. Cancer 2009, 9:798; Grivennikov & Karin, Cytokine & Growth Factor Rev.2010, 21:11). [0099] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [00100]Provided compounds are degraders and/or inhibitors of STAT3 protein and are therefore useful for treating one or more disorders associated with activity of STAT3 protein. Thus, in certain embodiments, the present invention provides a method for treating a STAT3-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. [00101]As used herein, the term “STAT3-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which STAT3 or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which STAT3 or a mutant thereof, are known to play a role. [00102] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder. [00103]Diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer (see, e.g., Turkson & Jove, Oncogene 2000, 19:6613-6626), diabetes (see, e.g., Gurzov et al., FEBS 2016, 283:3002), cardiovascular disease (see, e.g., Grote et al., Vasc. Pharmacol.2005, 43:2005), viral disease (see, e.g., Gao et al., J. Hepatol.2012, 57(2):430), autoimmune diseases such as lupus (see, e.g., Goropevšek et al., Clin. Rev. Alleg. & Immun.2017, 52(2):164), and rheumatoid arthritis (see, e.g., Walker & Smith, J. Rheumat.2005, 32(9):1650), autoinflammatory syndromes (see, e.g., Rauch et al., Jak-Stat 2013, 2(1):e23820), atherosclerosis (see, e.g., Ortiz-Muñoz et al., Arterio., Thrombo., Vasc. Bio.2009, 29:525), psoriasis (see, e.g., Andrés et al., Exp. Derm.2013, 22(5):323), allergic disorders (see, e.g., Oh et al., Eur. Respir. Rev.2019, 19(115):46), inflammatory bowel disease (see, e.g., Sugimoto, World J. Gastroenterol.2008, 14(33):5110), inflammation (see, e.g., Tamiya et al., Arterio., Thrombo., Vasc. Bio.2011, 31:980), acute and chronic gout and gouty arthritis, neurological disorders (see, e.g., Campbell, Brain Res. Rev.2005, 48(2):166), metabolic syndrome, immunodeficiency disorders such as AIDS and HIV (see, e.g., O’Shea et al., N. Engl. J. Med.2013, 368:161), destructive bone disorders (see, e.g., Jatiani et al., Genes & Can.2011, 1(10):979), osteoarthritis, proliferative disorders, Waldenström’s Macroglobulinemia (see, e.g., Hodge et al., Blood 2014, 123(7):1055) infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders in a patient. In one embodiment, a human patient is treated with a compound of the current invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably degrade and/or inhibit one or more STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6, or a mutant thereof [00104]Compounds of the current invention are useful in the treatment of a proliferative disease selected from a benign or malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkin’s and Non-Hodgkin’s, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, Smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). [00105] In some embodiments, the aberrant activation of STAT3 which can be treated according to the methods of this invention is a human cancer. In some embodiments, the human cancer which can be treated according to the methods of this invention is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), and pancreatic cancer. In some embodiments, abnormal STAT3 activation also correlates with the progression of diverse hematopoietic malignancies, such as various leukemias and lymphomas, and STAT3 is frequently activated in both multiple myeloma cell lines and tumor cell lines derived from patient bone marrows. [00106] In some embodiments, the present invention provides a method of treating a cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC) including EGFR-mutant NSCLC, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes. [00107] In some embodiments, the present invention provides a method of treating a JAK-associated disease. In some embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia Such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example CTCLs include Sezary syndrome and mycosis fungoides. [00108] In some embodiments, the present invention provides a method of treating a hematologic malignancy selected from LGL leukemia (T and NK cell), cutaneous T cell lymphoma (CTCL), peripheral T cell lymphomas (PTCL, all subtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acute myelogenous leukemia, multiple myeloma, and myelofibrosis. [00109] In some embodiments, the present invention provides a method of treating triple negative breast cancer in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00110] In some embodiments, the present invention provides a method of treating malignant peripheral nerve sheath tumors (MPNST) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00111] In some embodiments, the present invention provides a method of treating lung cancer in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00112] In some embodiments, the present invention provides a method of treating NSCLC in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00113] In some embodiments, the present invention provides a method of treating EGFR-mutant NSCLC in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00114] In some embodiments, the present invention provides a method of treating colorectal cancer in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00115] In some embodiments, the present invention provides a method of treating peripheral T-cell lymphoma in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [00116] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0100] Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma exacerbated or induced following bacterial or viral infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. [0101] Compounds according to the invention are useful in the treatment of heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis. [0102] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy. [0103] Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. [0104] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hyper eosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction. [0105] Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin. [0106] Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis. [0107] In some embodiments, the present invention provides a method of treating an autoimmune disease selected from encephalomyelitis, systemic sclerosis, idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, graft versus host disease (acute and chronic), and other tissue fibrosis diseases. [0108] In some embodiments, the present invention provides a method of treating autoimmune encephalomyelitis in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0109] In some embodiments, the present invention provides a method of treating tissue fibrosis or chronic tissue disease, including liver and kidney fibrosis, in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0110] In some embodiments, the present invention provides a method of treating idiopathic interstitial pneumonia(s) (IIPs), including any type of lung fibrosis, either interstitial lung disease associated with rheumatic disease (including SSc) or IPF itself, in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0111] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a disease of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin. [0112] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), and osteoarthritis. [0113] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease or TH17-associated disease. In some embodiments the TH17 mediated disease or TH17-associated disease is selected from psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis), or graft-versus-host disease. [0114] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis. [0115] In some embodiments, the present invention provides a method of treating an autoimmune disease or inflammatory disorder is selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic autoimmune hepatitis, progressive fibrosis associated interstitial lung disease, pulmonary arterial hypertension (PAH), immunoglobulin G4-related disease (IgG4-RD), chronic organ rejection (e.g., lung transplant), vasculitides (e.g., vasculitis), and STAT3 gain of function (GOF) mutations. [0116] In some embodiments, the present invention provides a method of treating nonalcoholic fatty liver disease (NAFLD) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of treating nonalcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD and NASH, a fatty-liver disease associated with liver fibrosis, are considered part of the same continuum that results finally in cirrhosis or HCC. [0117] In some embodiments, the present invention provides a method of treating idiopathic autoimmune hepatitis in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0118] In some embodiments, the present invention provides a method of treating progressive fibrosis associated interstitial lung disease in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0119] In some embodiments, the present invention provides a method of treating pulmonary arterial hypertension (PAH) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0120] In some embodiments, the present invention provides a method of treating immunoglobulin G4- related disease (IgG4-RD) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0121] In some embodiments, the present invention provides a method of treating chronic organ rejection (e.g., lung transplant) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0122] In some embodiments, the present invention provides a method of treating vasculitides (e.g., vasculitis) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. [0123] In some embodiments, the present invention provides a method of treating STAT3 gain of function (GOF) mutations in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT3 gain of function (GOF) mutations may be associated with a persistent activation of STAT3 signaling. In some embodiments, the clinical phenotype of STAT3 GOF-induced immune dysregulation may include one or more of IPEX-like, ALPS-like, and STAT5b-deficiency–like symptoms including lymphoproliferation and autoimmunity with prominent cytopenia, multi-organ autoimmunity (dermatitis, gastroenteritis, etc.), infections and immune deficiency characterized by hypo-IgG and reduced B cells. (Haddad et al., Blood 2015; Milner JD et al., 2015 Blood; Forbes LR et al., Curr Opin Hematol.2016). [0124] Cardiovascular diseases which can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis. [0125] In some embodiments, the neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease. [0126] In some embodiments the invention provides a method of treating, preventing or lessening the severity of Alzheimer’s disease comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt or composition thereof. [0127] In some embodiments the invention provides a method of treating a disease or condition commonly occurring in connection with transplantation. In some embodiments, the disease or condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease. [0128] In some embodiments the invention provides a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity. [0129] In some embodiments the invention provides a method of treating a viral disease. In some embodiments, the viral infection is HIV or COVID19 infection. [0130] Furthermore, the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation. EXEMPLIFICATION Example 1. Metabolite Identification of Compound A in Rat, Dog, Monkey, and Human Liver Microsomes [0131] Parent Compound A was incubated in rat, dog, monkey, and human liver microsome suspensions. As shown in Table 2 and Table 3 below, five metabolites were detected using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Preliminary metabolite identification indicated that parent Compound A underwent the biotransformation pathways of mono-oxidation and dehydrogenation. Table 2. Metabolites of Compound A in Various Liver Microsomes

Table 3. Proposed Metabolites of Parent Compound A in Liver Microsomes

Example 2. Metabolite Identification of Compound A in Rat, Dog, Monkey, and Human Blood [0132] Parent Compound A (0.5 and 10 ^M) was incubated in rat, dog, monkey, and human blood for 120 minutes. The percent remaining of the parent compound was 77%, 46.8%, 62.4% and 65.3% in rat, dog, monkey and human blood respectively. No metabolites were identified in dog, monkey or human blood. As shown in Table 4 and Table 5 below, a hydrolysis metabolite, M6, was detected using liquid chromatography–high-resolution mass spectrometry (LC-HRMS) in rat blood. Compound A was found to be generally stable in human, dog, and monkey blood. The apparent loss of compound in dog, monkey and human incubations may be attributed to non-specific binding of the parent compound to the incubation plate or sample collection tubes. Table 4. Metabolites of Compound A in Various Blood Species

BDL = below detection limit Table 5. Proposed Metabolite of Parent Compound A in Rat Blood

[0133] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of formula I:

provided that when

least A² is =O, OGluc, or OManNAc or at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OH, OGluc, or OManNAc.

2. The compound of claim 1, wherein

.

3. The compound of claim 1, wherein A¹ is H.

4. The compound of claim 1 or claim 2, wherein said compound is any one of the following formulae:

¹

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is OH.

6. The compound of any one of claims 1-5, wherein one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R⁶², R⁶³, and R⁶⁴ is OH.

7. The compound of any one of claims 1-6, wherein one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is OH.

8. The compound of any one of claims 1-7, wherein one of R¹, R², R³, R⁴, R²⁵, R²⁶, and R²⁷ is OH.

9. The compound of any one of claims 1-8, wherein one of R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, and R⁶¹ is OH.

10. The compound of any one of claim 1-9, wherein said compound is: , ,

,

, , , ,

, , ,

,

,

11. A composition comprising a compound of any one of claims 1-10 and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 12. A method of degrading STAT3 in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of any one of claims 1-10, or a pharmaceutical composition thereof. 13. A method of treating a STAT3-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of any one of claims 1-10, or a pharmaceutical composition thereof. 14. The method according to claim 13, wherein the STAT3-mediated disorder, disease or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.