IRAK4 degraders and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same to treat IRAK4-mediated disorder, disease, or condition in a patient.

Description

IRAK4 DEGRADERS AND USES THEREOFREFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to International Application No. PCT / CN2023 / 108561, filed July 21. 2023, the contents of which is herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides compounds and methods useful for the modulation of interleukin- 1 receptor-associated kinase 4 (“IRAK4”) 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

[0003] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnonnal 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.

[0004] 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. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles.

[0005] Tire UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug -like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful asbiochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).

[0006] An ongoing need exists in the art for effective treatments for disease, especially autoinflammatory and autoimmune diseases with high unmet medical need. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target disease-associated proteins such as interleukin-1 receptor-associated kinase 4 (“IRAK4”) hold promise as therapeutic agents. Accordingly, there remains a need to find compounds that are IRAK4 degraders useful as therapeutic agents.

[0007] The present invention addresses the need for improved IRAK4 degraders and provides additional advantages. SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of A1, A2, 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, and R47is as defined herein.

[0009] 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 signalingpathways implicating IRAK4 kinase. Such diseases, disorders, or conditions include those described herein.

[0010] 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 INVENTION1. General Description of Certain Aspects of the Invention

[0011] Tire 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 IRAK4 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. In some embodiments, a provided compound degrades and / or inhibits IRAK4.

[0012] In one aspect, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:B1is H, Glue, or ManNAc;B2is H, Glue, or ManNAc;A2is H, CR9R10R11, or Gluc; 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, R45, R46, and R47is independently H, OH, OGluc, or OManNAc; provided that at least B1or B2is 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, R44, R45, R46, and R47is OH, OGluc, or OManNAc.

[0013] In one aspect, the present invention provides a compound of formula II: or a pharmaceutically acceptable salt;B2is H, Gluc, or ManNAc; A2is H, CR9R10R11, Gluc, or ManNAc; A3is H, Gluc, or ManNAc; and each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is independently H, OH, OGluc, or OManNAc.

[0014] In one aspect, the present invention provides a compound of formula III:or a pharmaceuticallA4is H, Gluc, or ManNAc; each of 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, and R47is independently H, OH, OGluc, or OManNAc. 2. Definitions

[0015] 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).

[0016] As used herein, Compound A is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3- (difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, of formula:Compound A. pharmaceutically acceptable salts thereof, crystal forms thereof, and formulations thereof can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2020 / 010227, WO 2021 / 247899, and WO 2022 / 174268, the contents of which are incorporated herein by reference in their entireties.

[0017] As used herein, “Glue” refers to a glucuronide derivative, i.e.: luc” refers to a glucuronide ether derivative, i.e.:

[0019] As used herein, “ManNAc” refers to an N-Acetylmannosamine derivative, i.e. :

[0020] As used herein, “OManNAc” refers to an N-Acetylmannosamine ether derivative, i.e.:

[0021] 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,75thEd. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March ’s Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0022] Tire 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.

[0023] 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.

[0024] “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.

[0025] 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.

[0026] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0027] 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 thisinvention 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 pharmacally acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, 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, / Holucncsulfonatc. undecanoate, valerate salts, and the like.

[0028] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i 4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmacally acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations fonned using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0029] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or confonnational)) fonns of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E confonnational 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 fonns of the compounds of the invention are within the scope of the invention.

[0030] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits an IRAK kinase with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 pM. less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0031] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and / or inhibits both an IRAK kinase and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of the IRAK kinase. In certain embodiments, a degrader has an DCso of lessthan about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0032] Tire terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in an IRAK protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and an IRAK protein kinase, and an equivalent sample comprising an IRAK protein kinase, in the absence of said compound, or composition thereof.3. Description of Exemplary CompoundsFormula I

[0033] According to one aspect, the present invention provides a compound of formula I:I or a pharmaceutically acceptable salt thereof, wherein:B1is H, Glue, or ManNAc;B2is H. Glue, or ManNAc;A2is H, CR9R10Rn, Glue, 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, R24R25R26R27R28R29R3CR31R32R33R34R35R36R37R38R39R40R41R42R43R44R45, R46. and R47is independently H, OH, OGluc, or OManNAc;provided that at least B1or B2is Glue or ManNAc, or at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, Rlu, R11R12R13R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32, R33, R34, R35, R36, R37. R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47is OH, OGluc, or OManNAc.

[0036] As defined above and described herein, B1is H, Glue, or ManNAc.

[0037] In some embodiments, B1is H. In some embodiments, B1is Glue. In some embodiments, B1is ManNAc.

[0038] As defined above and described herein, B2is H, Glue, or ManNAc.

[0039] In some embodiments, B2is H. In some embodiments, B2is Glue. In some embodiments, B2is ManNAc.

[0040] As defined above and described herein, A2is H, CR9R10Rn, Glue, or ManNAc.

[0041] In some embodiments, A2is H. In some embodiments. A2is CR9R10Ru. In some embodiments, A2is Glue. In some embodiments. A2is ManNAc.

[0042] As defined above and described herein, each of R1, R2, R3, R4, R5, R5, R7, R8, R9, R10, R11, R12, R13,R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38, R39, R40, R41, R42, R43. R44, R45, R46, and R47is independently H. OH, OGluc, or OManNAc:

[0043] In some embodiments, one of R1, R2, R3, R4. R5. R6, R7, R8, R9, Rlu, R1 1, R12. R13, R14, R15, R16. R17, Ri8 R19R20R21R22R23R24R25R7R27R28R29R30R31R32R33R34R35R36R37R3SR39R40R41R42, R43, R44, R45, R46, and R47is OH.

[0044] In some embodiments, one of R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30is OH.

[0045] In some embodiments, one of R37. R38, R39, R40, R41. R42, R43, R44, R45, R4b, and R47is OH.

[0046] In some embodiments, one of R1, R2, R3, R4. R5. R6, R7, R8, R9, Rlu, R1 1, 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, and R37is OH.

[0047] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R1 1, R12, R13, R14, R1’, R16, R17,R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39R40R41R42, R43, R44, R45, R46, and R47is OGluc.

[0048] In some embodiments, one of R1, R2, R3, R4. R5, R6, R7, R8, R9, Rlu, R11, R12. R13, R14, R15, R16. R17, R1S R19 R20 R21 R22 R23 R24 p25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39 R40 R41R42, R43, R44, R45, R46, and R47is OManNAc.

[0049] In some embodiments, R1is H. In some embodiments, R2is H. In some embodiments, R3is H. In some embodiments, R4is H. In some embodiments, R5is H. In some embodiments, R6is H. In some embodiments, R7is H. In some embodiments, R8is H. In some embodiments, R9is H. In some embodiments, R10is H. In some embodiments, R11is H. In some embodiments, R12is H. In some embodiments. R13is H. In some embodiments. R14is H. In some embodiments. R13is H. In some embodiments, R16is H. In some embodiments, R17is H. In some embodiments, R18is H. In some embodiments, R19is H. In some embodiments, R20is H. In some embodiments, R21is H. In some embodiments, R22is H. In some embodiments, R23is H. In some embodiments, R24is H. In some embodiments, R25is H. In some embodiments, R26is H. In some embodiments, R27is H. In some embodiments, R28is H. In some embodiments, R29is H. In some embodiments, R30is H. In some embodiments. R31is H. In some embodiments. R32is H. In some embodiments. R33is H. In some embodiments, R34is H. In some embodiments, R35is H. In some embodiments, R36is H. In some embodiments, R37is H. In some embodiments, R38is H. In some embodiments, R39is H. In some embodiments, R40is H. In some embodiments, R41is H. In some embodiments, R42is H. In someembodiments, R43is H. In some embodiments, R44is H. In some embodiments, R45is H. In some embodiments, R46is H. In some embodiments, R47is H.

[0050] In some embodiments, R1is OH. In some embodiments, R2is OH. In some embodiments, R3is OH. In some embodiments, R4is OH. In some embodiments, R5is OH. In some embodiments, R6is OH.In some embodiments, R7is OH. In some embodiments, R8is OH. In some embodiments, R9is OH. In some embodiments. R10is OH. In some embodiments, R11is OH. In some embodiments, R12is OH. In some embodiments, R13is OH. In some embodiments, R14is OH. In some embodiments, R15is OH. In some embodiments, R16is OH. In some embodiments, R17is OH. In some embodiments, R18is OH. In some embodiments, R19is OH. In some embodiments, R20is OH. In some embodiments, R21is OH. In some embodiments, R22is OH. In some embodiments, R23is OH. In some embodiments, R24is OH. In some embodiments, R25is OH. In some embodiments, R26is OH. In some embodiments, R27is OH. In some embodiments. R28is OH. In some embodiments. R29is OH. In some embodiments. R30is OH. In some embodiments, R31is OH. In some embodiments, R32is OH. In some embodiments, R33is OH. In some embodiments, R34is OH. In some embodiments, R35is OH. In some embodiments, R36is OH. In some embodiments, R37is OH. In some embodiments, R38is OH. In some embodiments, R39is OH. In some embodiments, R40is OH. In some embodiments, R41is OH. In some embodiments, R42is OH. In some embodiments, R43is OH. In some embodiments, R44is OH. In some embodiments, R45is OH. In some embodiments. R46is OH. In some embodiments, R47is OH.

[0051] In some embodiments, R1is OGluc. In some embodiments, R2is OGluc. In some embodiments, R3is OGluc. In some embodiments, R4is OGluc. hi some embodiments, R5is OGluc. In some embodiments, R6is OGluc. In some embodiments, R7is OGluc. In some embodiments, R8is OGluc. In some embodiments, R9is OGluc. In some embodiments, R10is OGluc. In some embodiments, R11is OGluc. In some embodiments, R12is OGluc. In some embodiments, R13is OGluc. In some embodiments, R14is OGluc. In some embodiments. R13is OGluc. In some embodiments, R16is OGluc. In some embodiments, R17is OGluc. In some embodiments, R18is OGluc. In some embodiments, R19is OGluc. In some embodiments, R20is OGluc. In some embodiments, R21is OGluc. In some embodiments, R22is OGluc. In some embodiments, R23is OGluc. In some embodiments, R24is OGluc. In some embodiments, R25is OGluc. In some embodiments, R26is OGluc. In some embodiments, R27is OGluc. In some embodiments, R28is OGluc. In some embodiments, R29is OGluc. In some embodiments. R30is OGluc. In some embodiments, R31is OGluc. In some embodiments. R32is OGluc. In some embodiments. R33is OGluc. In some embodiments, R34is OGluc. In some embodiments, R35is OGluc. In some embodiments.R3’ is OGluc. In some embodiments, R37is OGluc. In some embodiments, R38is OGluc. In some embodiments, R39is OGluc. In some embodiments, R40is OGluc. In some embodiments, R41is OGluc.In some embodiments, R42is OGluc. In some embodiments, R43is OGluc. In some embodiments, R44is OGluc. In some embodiments, R43is OGluc. In some embodiments, R46is OGluc. In some embodiments, R47is OGluc.

[0052] In some embodiments, R1is OManNAc. In some embodiments, R2is OManNAc. In some embodiments, R3is OManNAc. In some embodiments, R4is OManNAc. In some embodiments, R5is OManNAc. In some embodiments. R6is OManNAc. In some embodiments, R7is OManNAc. In some embodiments, R8is OManNAc. In some embodiments, R9is OManNAc. In some embodiments, R10is OManNAc. In some embodiments, R11is OManNAc. In some embodiments, R12is OManNAc. In some embodiments, R13is OManNAc. In some embodiments, R14is OManNAc. In some embodiments, R15is OManNAc. In some embodiments, R16is OManNAc. In some embodiments, R17is OManNAc. In some embodiments, R18is OManNAc. In some embodiments, R19is OManNAc. In some embodiments. R20is OManNAc. In some embodiments, R21is OManNAc. In some embodiments, R22is OManNAc. In some embodiments, R23is OManNAc. In some embodiments, R24is OManNAc. In some embodiments, R25is OManNAc. In some embodiments, R26is OManNAc. In some embodiments, R27is OManNAc. In some embodiments, R28is OManNAc. In some embodiments, R29is OManNAc. In some embodiments, R3C1is OManNAc. In some embodiments, R31is OManNAc. In some embodiments, R32is OManNAc. In some embodiments, R33is OManNAc. In some embodiments, R34is OManNAc. In some embodiments. R35is OManNAc. In some embodiments, R36is OManNAc. In some embodiments, R37is OManNAc. In some embodiments, R38is OManNAc. In some embodiments, R39is OManNAc. In some embodiments, R40is OManNAc. In some embodiments, R41is OManNAc. In some embodiments, R42is OManNAc. In some embodiments, R43is OManNAc. In some embodiments, R44is OManNAc. In some embodiments, R45is OManNAc. In some embodiments, R46is OManNAc. In some embodiments. R47is OManNAc.

[0053] In some embodiments, one OH is present in the compound of formula I or a pharmacally 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 Glue 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 tire compound of formula I or a pharmacally acceptable salt thereof. In some embodiments, one OManNAc is present in the compound of formula I or a pharmaceutically acceptable salt thereof.

[0054] Non-limiting examples of R*-R47combinations for formula I are shown in Table 1A below whereThe four parts of the Table, taken together, show examples ofR’-R47combinations.Table lA-Part 1: Exemplary formula I substituent combinations.Table lA-Part 2: Exemplary formula I substituent combinations.Table lA-Part 3: Exemplary formula I substituent combinations.Table lA-Part 4: Exemplary formula I substituent combinations.

[0055] Non-limiting examples of R'-R47combinations for formula I are shown in Table IB below whereTire four parts of the Table, taken together, show examples ofR’-R47combinations. In Table IB below. OG = OGluc.Table IB-Part 1: Exemplary formula I substituent combinations.Table IB-Part 2: Exemplary formula I substituent combinations.Table IB-Part 3: Exemplary formula I substituent combinations.Table IB-Part 4: Exemplary formula I substituent combinations.

[0056] Non-limiting examples of R'-R47combinations for fonnula I are shown in Table 1C below whereTire four parts of the Table, taken together, show examples ofR'-R47combinations. In Table 1C below, OM = OManNAc.Table IC-Part 1: Exemplary fonnula I substituent combinations.Table IC-Part 2: Exemplary formula I substituent combinations.Table IC-Part 3: Exemplary formula I substituent combinations.Table IC-Part 4: Exemplary formula I substituent combinations.

[0057] According to another aspect, the present invention provides a compound of formula I-a:I-a 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, R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39R40R41R42R43R44R45, R46. and R47is independently H, OH, OGluc, or OManNAc; provided that at least one of R1, R2, R3, R4, R5. R6. R7. R8, R9, R10. R11. R12, R13, R14. R15, R16, R17, R18. R19, R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39R40R41, R42, R43, R44, R45, R46, and R47is OH, OGluc, or OManNAc.

[0058] According to another aspect, the present invention provides a compound of formula I-b:or a pharmaceutically acceptable salt thereof, wherein: each of R37, R38, R39, R40, R41, R42. R43, R44, R45, R46. and R47is independently H, OH, OGluc, or OManNAc;provided that at least one of R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47is OH, OGluc, or OManNAc.

[0059] According to another aspect, the present invention provides a compound of formula I-c:I-c 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, R2S. R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, and R37is independently H, OH, OGluc, or OManNAc; provided that 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, and R37is OH, OGluc, or OManNAc.

[0060] 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, and R11is independently H, OH, OGluc, or OManNAc;provided that at least one of R1, R2, R3, R4, R\ R . R7, Rs, R9, R10, and R11is OH, OGluc, or OManNAc.

[0061] According to another aspect, the present invention provides a compound of formula I-e:I-e or a pharmaceutically acceptable salt thereof, wherein: each of R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, and R33is independently H, OH, OGluc, or OManNAc; provided that at least one of R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30. R31, R32, and R33is OH, OGluc, or OManNAc.

[0062] In some embodiments, the compound of fonnula I is:or a pharmaceutically acceptable salt thereof.

[0063] 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.Formula II

[0064] According to one aspect, the present invention provides a compound of formula II:or a pharmaceutically acceptable salt;B2is H, Gluc, or ManNAc; A2is H, CR9R10R11, Gluc, or ManNAc; A3is H, Gluc, or ManNAc; and each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is independently H, OH, OGluc, or OManNAc.

[0065] As defined above and described herein, A1is ,.or 1 is

[0068] In some embodiments, B1is H. In some embodiments, B1is Gluc. In some embodiments, B1is ManNAc.

[0069] As defined above and described herein, B2is H, Gluc, or ManNAc.

[0070] In some embodiments, B2is H. In some embodiments, B2is Gluc. In some embodiments, B2is ManNAc.

[0071] As defined above and described herein, A2is H, CR9R10R11, Gluc, or ManNAc.

[0072] In some embodiments, A2is H. In some embodiments, A2is CR9R10R11. In some embodiments, A2is Gluc. In some embodiments, A2is ManNAc.

[0073] As defined above and described herein, A3is H, Gluc, or ManNAc.

[0074] In some embodiments, A3is H. In some embodiments, A3is Gluc. In some embodiments, A3is ManNAc.

[0075] As defined above and described herein, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is independently H, OH, OGluc, or OManNAc;

[0076] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is OH.

[0077] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is OGluc.

[0078] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13is OManNAc.

[0079] In some embodiments, R1is H. In some embodiments, R2is H. In some embodiments, R3is H. In some embodiments, R4is H. In some embodiments, R5is H. In some embodiments, R6is H. In some embodiments, R7is H. In some embodiments, R8is H. In some embodiments, R9is H. In someembodiments, R10is H. In some embodiments, R11is H. In some embodiments, R12is H. In some embodiments, R13is H.

[0080] In some embodiments, R1is OH. In some embodiments, R2is OH. In some embodiments, R3is OH. In some embodiments, R4is OH. In some embodiments, R5is OH. In some embodiments, R6is OH. In some embodiments, R7is OH. In some embodiments, R8is OH. In some embodiments, R9is OH. In some embodiments, R10is OH. In some embodiments, R11is OH. In some embodiments, R12is OH. In some embodiments, R13is OH.

[0081] In some embodiments, R1is OGluc. In some embodiments, R2is OGluc. In some embodiments, R3is OGluc. In some embodiments, R4is OGluc. In some embodiments, R5is OGluc. In some embodiments, R6is OGluc. In some embodiments, R7is OGluc. In some embodiments, R8is OGluc. In some embodiments, R9is OGluc. In some embodiments, R10is OGluc. In some embodiments, R11is OGluc. In some embodiments, R12is OGluc. In some embodiments, R13is OGluc.

[0082] In some embodiments, R1is OManNAc. In some embodiments, R2is OManNAc. In some embodiments, R3is OManNAc. In some embodiments, R4is OManNAc. In some embodiments, R5is OManNAc. In some embodiments, R6is OManNAc. In some embodiments, R7is OManNAc. In some embodiments, R8is OManNAc. In some embodiments, R9is OManNAc. In some embodiments, R10is OManNAc. In some embodiments, R11is OManNAc. In some embodiments, R12is OManNAc. In some embodiments, R13is OManNAc.

[0083] In some embodiments, one OH is present in the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the OH present in the compound of formula II or a pharmaceutically acceptable salt thereof is present as an N-oxide. In some embodiments, one Gluc is present in the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, one OGluc is present in the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, one ManNAc is present in the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, one OManNAc is present in the compound of formula II or a pharmaceutically acceptable salt thereof.

[0084] Non-limiting examples of R1-R13combinations for formula II are shown in Table 2A below where H.binations.

[0085] Non-limiting examples of R'-R13combinations for formula II are shown in Table 2B below whereTable 2B below, OG = OGluc.Table 2B: Exemplary formula II substituent combinations.

[0086] Non-limiting examples of R'-R13combinations for formula II are shown in Table 2C below wheres Glue.Table 2C: Exemplary- fonnula II substituent combinations.

[0087] Non-limiting examples of R'-R13combinations for Formula II are shown in Table 2D below whereGlue. In Table 2D below. OG = OGluc.Table 2D: Exemplary- Formula II substituent combinations.

[0088] According to another aspect, the present invention provides a compound of formula II-a:II-a or a pharmaceutically acceptable salt thereof, wherein:A3is H, Glue, or ManNAc; and each of R1, R2, R6, R7, R8, R9, R10, and R11is independently H, OH, OGluc, or OManNAc; provided that at least A3is Glue or ManNAc and at least one of R1, R2, R6, R7, R8, R9, R10, and R11is OH, OGluc, or OManNAc.

[0089] According to another aspect, the present invention provides a compound of formula H-b:or a pharmaceutically acceptable salt thereof, wherein:A3is H, Glue, or ManNAc.

[0090] In some embodiments, the compound of fonnula II is:or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, a compound of formula II 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.Formula III

[0092] According to one aspect, the present invention provides a compound of formula III:or a pharmaceutically acceptable salt thereof, wherein:A4is H, Glue, or ManNAc; andeach of 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, and R47is independently H, OH, OGluc, or OManNAc.

[0093] As defined above and described herein, A4is H, Glue, or ManNAc.

[0094] In some embodiments, A4is H. In some embodiments, A4is Glue. In some embodiments, A4is ManNAc.

[0095] As defined above and described herein, each of R14, R15, Rlb, R17, R18, R19, R2U, 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, and R47is independently H, OH, OGluc, or OManNAc;

[0096] In some embodiments, one of 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, and R47is OH.

[0097] In some embodiments, one of R14, R13, R16, R17. R18, R19, R20. R21, R22, R23. R24. R2'. R26, R27. R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47is OGluc.

[0098] In some embodiments, one of 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, and R47is OManNAc.

[0099] In some embodiments, R1’ is H. In some embodiments, R16is H. In some embodiments, R17is H.In some embodiments, R18is H. In some embodiments, R19is H. In some embodiments, R20is H. In some embodiments. R21is H. In some embodiments. R22is H. In some embodiments. R23is H. In some embodiments, R24is H. In some embodiments, R25is H. In some embodiments, R26is H. In some embodiments, R27is H. In some embodiments, R28is H. In some embodiments, R29is H. In some embodiments, R30is H. In some embodiments, R31is H. In some embodiments, R32is H. In some embodiments, R33is H. In some embodiments, R34is H. In some embodiments, R35is H. In some embodiments, R36is H. In some embodiments, R37is H. In some embodiments, R38is H. In some embodiments. R39is H. In some embodiments. R40is H. In some embodiments. R41is H. In some embodiments, R42is H. In some embodiments, R43is H. In some embodiments, R44is H. In some embodiments, R45is H. In some embodiments, R46is H. In some embodiments, R47is H.

[0100] In some embodiments, R14is OH. In some embodiments, R15is OH. In some embodiments, R16isOH. In some embodiments, R17is OH. hi some embodiments, R18is OH. In some embodiments. R19isOH. In some embodiments, R2Uis OH. hi some embodiments, R21is OH. In some embodiments. R22isOH. In some embodiments, R23is OH. In some embodiments. R24is OH. In some embodiments. R2’ isOH. In some embodiments, R26is OH. In some embodiments, R27is OH. In some embodiments, R28isOH. In some embodiments, R29is OH. In some embodiments, R30is OH. In some embodiments, R31isOH. In some embodiments, R32is OH. In some embodiments, R33is OH. In some embodiments, R34isOH. In some embodiments, R35is OH. In some embodiments, R36is OH. In some embodiments, R37isOH. In some embodiments, R38is OH. In some embodiments, R39is OH. In some embodiments, R40isOH. In some embodiments, R41is OH. In some embodiments, R42is OH. In some embodiments, R43isOH. In some embodiments, R44is OH. In some embodiments, R45is OH. In some embodiments, R46isOH. In some embodiments, R47is OH.

[0101] In some embodiments, R14is OGluc. In some embodiments, Rlbis OGluc. In some embodiments, Rlbis OGluc. In some embodiments, R17is OGluc. In some embodiments, R1Sis OGluc. In some embodiments, R19is OGluc. In some embodiments, R20is OGluc. In some embodiments, R21is OGluc. In some embodiments, R22is OGluc. In some embodiments, R23is OGluc. In some embodiments, R24is OGluc. In some embodiments, R2is OGluc. In some embodiments, R2bis OGluc. In some embodiments, R27is OGluc. In some embodiments, R28is OGluc. In some embodiments, R29is OGluc. In some embodiments. R30is OGluc. In some embodiments, R31is OGluc. In some embodiments. R32is OGluc. In some embodiments, R33is OGluc. In some embodiments, R34is OGluc. In some embodiments, R35is OGluc. In some embodiments, R3bis OGluc. In some embodiments, R37is OGluc. In some embodiments, R38is OGluc. In some embodiments, R39is OGluc. In some embodiments, R40is OGluc. In some embodiments, R41is OGluc. hi some embodiments, R42is OGluc. In some embodiments, R43is OGluc. In some embodiments, R44is OGluc. In some embodiments, R45is OGluc. In some embodiments. R4bis OGluc. In some embodiments, R47is OGluc.

[0100] In some embodiments, R14is OManNAc. In some embodiments, Rlbis OManNAc. In some embodiments, R16is OManNAc. In some embodiments, R17is OManNAc. In some embodiments, R18is OManNAc. In some embodiments, R19is OManNAc. In some embodiments, R20is OManNAc. In some embodiments, R21is OManNAc. In some embodiments, R22is OManNAc. In some embodiments. R23is OManNAc. In some embodiments, R24is OManNAc. In some embodiments, R2’ is OManNAc. In some embodiments. R2bis OManNAc. In some embodiments, R27is OManNAc. In some embodiments. R28is OManNAc. In some embodiments, R29is OManNAc. In some embodiments, R30is OManNAc. In some embodiments, R31is OManNAc. In some embodiments, R32is OManNAc. In some embodiments, R33is OManNAc. In some embodiments, R34is OManNAc. In some embodiments, R35is OManNAc. In some embodiments, R36is OManNAc. In some embodiments, R37is OManNAc. In some embodiments. R38is OManNAc. In some embodiments, R39is OManNAc. In some embodiments, R4Uis OManNAc. In some embodiments. R41is OManNAc. In some embodiments, R42is OManNAc. In some embodiments. R43is OManNAc. In some embodiments, R44is OManNAc. In some embodiments, R45is OManNAc. In some embodiments, R46is OManNAc. In some embodiments, R47is OManNAc.

[0101] In some embodiments, one OH is present in the compound of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, tire OH present in the compound of formula III or a pharmaceutically acceptable salt thereof is present as an N-oxide. In some embodiments, one Glue is present in the compound of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, one OGluc is present in the compound of fonnula III or a pharmaceutically acceptable salt thereof. In some embodiments, one ManNAc is present in the compound of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, one OManNAc is present in the compound of formula III or a pharmaceutically acceptable salt thereof.

[0102] Non-limiting examples of R14-R47combinations for formula III are shown in Table 3 A below where A4is H. Tire three parts of the Table, taken together, show examples of R14-R47combinations.Table 3A-Part 1: Exemplary formula III substituent combinations.Table 3A-Part 2: Exemplary formula III substituent combinations.Table 3A-Part 3: Exemplary formula III substituent combinations.

[0103] Non-limiting examples of R14-R47combinations for formula III are shown in Table 3B below where A4is H. The three parts of the Table, taken together, show examples of R14-R47combinations. In Table 3B below, OG = OGluc.Table 3B-Part 1: Exemplary formula III substituent combinations.Table 3B-Part 2: Exemplary formula III substituent combinations.Table 3B-Part 3: Exemplary formula III substituent combinations.

[0104] Non-limiting examples of R14-R47combinations for formula III are shown in Table 3C below where A4is Glue. The three parts of the Table, taken together, show examples of R14-R47combinations. Table 3C-Part 1: Exemplary fonnula III substituent combinations.Table 3C-Part 2: Exemplary formula III substituent combinations.Table 3C-Part 3: Exemplary formula III substituent combinations.

[0105] Non-limiting examples of R14-R47combinations for formula III are shown in Table 3D below where A4is Glue. Tire three parts of the Table, taken together, show examples of R14-R47combinations. In Table 3D below, OG = OGluc.Table 3D-Part 1: Exemplary formula III substituent combinations.Table 3D-Part 2: Exemplary formula III substituent combinations.Table 3D-Part 3: Exemplary formula III substituent combinations.

[0106] According to another aspect, the present invention provides a compound of formula Ill-a:or a pharmaceutically acceptable salt thereof, wherein: A4is H, Gluc, or ManNAc; each of R14, R15, R16, R17, R18, R19, R20, and R21is independently H, OH, OGluc, or OManNAc.

[0107] According to another aspect, the present invention provides a compound of formula III-b:or a pharmaceutically acceptable salt thereof, wherein: A4is H, Gluc, or ManNAc;

[0108] In some embodiments, the compound of formula III is:or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, a compound of fonnula III 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

[0110] 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. Hie amount of compound in compositions of this invention is such that is effective to measurably degrade and / or inhibit an IRAK protein kinase, 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 an IRAK protein kinase, 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.

[0111] The term ‘'patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0112] Tire 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.

[0113] 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.

[0114] As used herein, the term "inhibitory active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of an IRAK protein kinase, or a mutant thereof.

[0115] As used herein, the term "degradatory active metabolite or residue thereof means that a metabolite or residue thereof is also a degrader of an IRAK protein kinase, or a mutant thereof.

[0116] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Tire term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular. intra-synovial, intrastemal. 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.

[0117] 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 usefid in the preparation of injectables, as are natural pharmacally-acceptable oils, such as olive oil or castor oil, especially in their polyoxyetirylated 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.

[0118] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage fomr 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 com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, usefid 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.

[0119] 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.

[0120] Pharmacally 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 tire eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0121] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema fonnulation. Topically-transdermal patches may also be used.

[0122] For topical applications, provided pharmaceutically acceptable compositions may be fonnulated 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 ormore 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.

[0123] 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 benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0124] 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 pharmacal 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.

[0125] 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.

[0126] Hie 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.

[0127] 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. Exemplary Methods and Uses

[0128] Compounds and compositions described herein are generally useful for the degradation and / or inhibition of kinase activity of IRAK4. In certain embodiments, the present invention provides a methodof treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a provided compound, or a pharmaceutical composition thereof.

[0129] In some embodiments, the present invention provides a method for treating an autoimmunc / autoinflammatory disease or a hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the IRAK4-mediated disorder, disease, or condition is an autoimmunc / autoinflammatory disease or a hematological malignancy. In some embodiments, the autoimmune / automflammatory disease is a cutaneous autoimmune / autoinflammatory disease.

[0130] In some embodiments, the autoimmune / autoinflammatory disease includes inflammatory or allergic conditions of the skin, for example psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dennatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet Syndrome, pyoderma gangrenosum, and other inflammatory or allergic conditions of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dennatitits, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, or hidradenitis suppurativa.

[0131] In some embodiments, a provided compound 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, uveitis (anterior and posterior), Sjogren's syndrome,keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung 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, bronchitis, 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, 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.

[0132] 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), adult onset Still’s disease, macrophage activation syndrome (MAS), primary and secondary hemophagocytic lymph histiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.

[0133] In some embodiments the inflammatory disease which can be treated is a TH 17 mediated disease. In some embodiments the TH17 mediated disease is selected from systemic lupus erythematosus, multiplesclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[0134] In some embodiments tire 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 or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0135] In some embodiments, the present disclosure provides a method for treating a cutaneous autoimmune / autoinflammatory disease in a patient, such as atopic dermatitis (AD) and hidradenitis suppurativa (HS), comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the present disclosure provides a method for treating AD in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the present disclosure provides a method for treating HS in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis (RA) in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the present disclosure provides a method for treating hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the hematological malignancy is leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL. chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma. Burkitt lymphoma / leukemia, acute ly mphocy tic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, or MDS.

[0140] The following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.EXEMPLIFICATIONExample 1. Metabolite Identification of Compound A in Liver Microsomes from Human and Preclinical Species

[0141] Objective: The objective of this study was to identify the potential metabolites of Compound A in liver microsomes from rat, dog, monkey and human.

[0142] Method: Compound A was incubated with rat, dog, monkey and human liver microsomes. The test concentration of Compound A was 10 pM. Samples were taken at 0, 30 and 60 minutes, respectively. Metabolite profiling was carried out using UPLC-MS / MS with data dependent acquisition (DDA) of MS / MS scan spectra trigger by full MS scan.

[0143] Results: Three metabolites of Compound A were detected in rat, dog, monkey and human liver microsomes samples. Metabolites generated in liver microsome from human were also detected in those from rat, dog, and monkey. As shown in Table 4, the primary metabolic pathway was dealkylation of the linker in the parent drug and a minor oxidative metabolite was also formed on the dealkylation product.Table 4. Metabolites of Compound in Liver Microsomesnot observed

[0144] Tire proposed metabolic pathways of Compound A is shown in the following scheme.

[0145] Conclusions: Three metabolites of Compound A were detected following 1-hour incubation in liver microsomes from rat, dog, monkey and human. Metabolites generated in liver microsome from human were also detected in those from rat, dog, and monkey. The primary metabolic pathway was dealkylation in the linker region of the parent drug.Example 2. Plasma Metabolite Identification after Single Dose Oral Administration of Compound A in Rats

[0146] Objective: Hie objective of this study was to identify the potential major circulating metabolites in plasma following single oral administration of Compound A in rats.

[0147] Method: Rat plasma PK study samples following single dose 100 mg / kg oral administration were used for metabolite profiling analysis using the Hamilton pooling method. The pooled plasma samples were analyzed by LC-MS / MS using the data dependent acquisition (DDA) mode.

[0148] Results: Parent drug, Compound A, is the main constituent in rat plasma, accounting for 60% of the peak areas. As shown in Table 5, three circulating metabolites, M2, M4, and M5, were detected, account for 11%, 21%, and 7% of the peak areas. M2, a dealkylation metabolite, was also observed in the liver microsomal incubation with Compound A. M4 and M5 were proposed as two oxidative metabolites of the parent drug.Table 5. Metabolites of Compound in Rat Plasma at 100 mg / kg.

[0149] The proposed metabolic pathways of Compound A is shown in the following scheme.

[0150] Conclusions: Following oral administration of Compound A at 100 mg / kg in rats, parent drug is the main constituent in rat plasma. Three circulating metabolites were detected, including a dealkylation metabolite (M2), which was observed in the liver microsomal incubation, and two proposed mono-oxidative metabolites of the parent drug.Example 3. Plasma Metabolite Identification after Single Dose Oral Administration of Compound A in Dogs

[0151] Objective: Hie objective of this study was to identify the potential major circulating metabolites in plasma following oral administration of Compound A in dogs.

[0152] Method: Dog plasma PK study samples following single dose 150 mg / kg oral administration were used for metabolite profiling analysis using the Hamilton pooling method. Tire pooled plasma samples were analyzed by LC-MS / MS using the data dependent acquisition (DDA) mode.

[0153] Results: Parent drug, Compound A, is the main constituent in the dog plasma, accounting for 73% of the peak areas. As shown in Table 6, one circulating metabolite, M2, was detected, account for 27% of the peak areas. M2, a dealkylation metabolite, was also observed in the liver microsomal incubation rat, dog, and human.Table 6. Metabolites of Compound in Dog Plasma at 150 mg / kg.

[0154] The proposed metabolic pathways of Compound A is shown in the following scheme.

[0155] Conclusions: Following oral administration of Compound A at 150 mg / kg in dogs, parent drag is the main constituent in dog plasma, accounting for 73% of the peak areas from LC-MS analysis. One circulating metabolite, resulted from oxidative dealkylation metabolism, was detected. Tire circulating metabolite was also observed in the liver microsomal incubation from rat, dog, and human, and in rat plasma.

[0156] 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: R23, 4,, 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, and R47is OH, OGluc, or OManNAc.The compound of claim 1, wherein3. The compound of claim 1, whereinThe compound of claim 1, wherein5. The compound of claim 1 or claim 2, wherein said compound is any one of the following formulae:I-aor a phar6. 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, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47is OH.

7. The compound of any one of claims 1-6, 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, and R47is OGluc.

8. The compound of any one of claims 1-7, 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, R33,10. A compound of formula II:or a pharmaceutically acceptable salt thereof, wherein:B1is H, Glue, or ManNAc;B2is H, Glue, or ManNAc;A2is H, CR9R10Rn, Glue, or ManNAc;A3is H, Glue, or ManNAc; and each of R1, R2, R3. R4, R5, R6, R7, R8, R9, Rlu, R11, R12. and R13is independently H, OH, OGluc, orOManNAc.

11. The compound of claim 10, whereinTire compound of claim 10, whereinThe compound of claim 10, wherein14. The compound of claim 10 or claim 11, wherein said compound is any one of the following formulae:Il-b or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 10-14, wherein one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rn, R12, and R13is OH.

16. The compound of any one of claims 10-15, wherein one of R1, R2, R3, R4, R\ R6, R7, R8, R9, R10, R11, R12, and R13is OGluc.

17. The compound of any one of claims 10-16, wherein one of R1, R2, R3. R4, R5, R6, R7, R8, R9, R10, R11, R12. and R13is OManNAc.

18. The compound of any one of claims 10-15, wherein said compound is:or a pharmaceutically acceptable salt thereof.

19. A compound of formula III:III or a pharmaceutically acceptable salt thereof, wherein:A4is H, Glue, or ManNAc; each of R14, R15. R16, R17, R1 S, 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, and R47is independently H, OH, OGluc, or OManNAc.

20. The compound of claim 19, wherein A4is H or Glue.

21. Tire compound of claim 19 or claim 20, wherein said compound is one of the following fonnulae:Ill-b or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 19-21, wherein one of R14, R15. Rlb, 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, and R47is OH.

23. The compound of any one of claims 19-22, wherein one of 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. and R47is OGluc.

24. The compound of any one of claims 19-23, wherein one of 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, and R47is OManNAc.

25. The compound of any one of claims 19-24, wherein said compound is: ,26. A composition comprising a compound of any one of claims 1-25 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

27. A method of degrading IRAK4 protein kinase in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of any one of claims 1-25, or a pharmaceutical composition thereof.

28. A method of treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of any one of claims 1-25, or a pharmaceutical composition thereof.

29. The method according to claim 28, wherein the IRAK4-mediated disorder, disease or condition is an autoimmune / autoinflammatory disease or a hematological malignancy.