Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to compounds and methods useful for the modulation of one or more interleukin-1 receptor-associated kinases (“IRAK”) via ubiquitination and/or degradation by compounds according to the present invention.
• IRAK interleukin-1 receptor-associated kinases
• the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
• Ubiquitin-Proteasome Pathway 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.
• E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled“Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.
• 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.
• the 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 as biochemical 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).
• the present application relates novel bifunctional compounds, which function to recruit IRAK kinases to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof.
• the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of IRAK kinases, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
• monovalent compounds which find utility as inducers of targeted ubiquitination of IRAK kinases, which are then degraded and/or otherwise inhibited by the monovalent compounds as described herein.
• An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of IRAK kinases.
• the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., multiple myeloma.
• the present application further relates to targeted degradation of IRAK kinases through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds IRAK kinasses.
• Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating IRAK kinases. Such diseases, disorders, or conditions include those described herein.
• Compounds provided by this invention are also useful for the study of IRAK enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new IRAK inhibitors or IRAK degraders or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.
• FIG.1 is an image showing a western blot of degrader I-30 in OCI-LY10 at 24 h.
• FIG. 2 is an image of a dose response curve for IKAK4 (% control)(y-axis) versus degrader I-30 concentration ( ⁇ M) (x-axis) for OCI-LY10 and TMD8 cell lines and in vitro degradation results (DC 90 , ⁇ M).
• FIG.3 is an image of a deep TMT proteomics scatterplot in OCI-LY10 at 8h showing Log2 FC 10 nM degrader I-30 in DMSO (y-axis) and Log2 FC 10 nM degrader in DMSO Rep1 (x-axis).
• FIG.4 includes graphical images showing the decrease of IRAK4 at 24h with count (y- axis) versus IRAK (MFI) (x-axis) using several concentrations of degrader I-30 (A); the time dependent induction of apoptosis with 50 nM degrader I-30 showing IRAK4 (% control) (left y- axis) and cleaved CASP3 (% control) (right y-axis) versus time (h) (x-axis) (B); the inhibition of cell proliferation at 72 h showing count (y-axis) versus Ki67 (MFI) (x-axis) at several concentrations of degrader I-30 (C); and the induction of apoptosis is mechanism specific showing cleaved CASP3 (% control) (y-axis) for degrader I-30 and inactive (x-axis) at several concentrations respectively (D).
• FIG. 5 shows the results (CTG; IC50 in ⁇
• SC, QD degrader I-30
• FIG.7 is a graphical image of xenograph results for vehicle (PO, BID) and degrader I- 30 (PO, BID: 10 mg/kg; 30 mg/kg; and 100 mg/kg) showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.8 is a graphical image showing in vivo degradation of IRAK4 in BALB/c mouse spleen following three PO doses of degrader I-30 depicted as IRAK4 (% control) (y-axis) and PO doses (10 mg/kg; 30 mg/kg; and 100 mg/kg) (x-axis).
• FIG.9 is a graphical image depicting neotrophils in exudate collected from air pouch in mouse following MSU crystal challenge using showing neutrophiles count (% cells in extrudate) (y-axis) and (MSU; colchicine, 1 mg/kg SC; anakinra, 100 mg/kg SC; and PO I-30 doses: 10 mg/kg; 30 mg/kg; and 100 mg/kg) (x-axis).
• FIG.10 is an image of a dose response curve for IKAK4 (% control) (y-axis) versus degrader I-30 concentration (uM) (x-axis) for OCI-LY10 cell lines and in vitro degradation results (DC 90 , ⁇ M).
• FIG. 11 is a graphical image showing oral degrader I-75 exposure in mouse with degrader concentration in plasma (ng/mL) (y-axis) over time (hours) (x-axis) at doses of 30 mg/kg, 100 mg/kg, and 300 mg/kg (A), PK characteristics in CD1 mice (B), and oral bioavailability across species (C).
• FIG.12 is are graphical image showing apoptosis in OCI-LY10 at 72h with Apoptotic Cells (CC3 + /CPARP + , % Control) (y-axis) over several concentrations of 2 nM ibrutinib, degrader I-30, and the combination of 2 nM ibrutinib and degrader I-30 ( ⁇ M) (x-axis) (A); and the graphical results of a Cell Titer Glo assay showing synergism (B).
• FIG. 13 is a graphical image of in vivo xenograph results for vehicle (PO, QD), degrader I-30 (PO, QD, 25 mg/kg), ibrutinib (PO, QD, 25 mg/kg), and degrader + ibrutinib (PO, QD: 25 + 25 mg/kg), showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 L265P, CD79 mutant) cells.
• PO, QD vehicle
• degrader I-30 PO, QD, 25 mg/kg
• ibrutinib PO, QD, 25 mg/kg
• degrader + ibrutinib PO, QD: 25 + 25 mg/kg
• FIG.14 is a graphical image of in vivo xenograph results for vehicle (10% TPGS in water, PO, QD) and degrader I-75 (PO, QD: 25 mg/kg and 50 mg/kg) showing tumor volume (mm 3 )(y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.15 is a graphical image of in vivo IL-1b testing following MSU crystal challenge showing IL-1b in plasma (pg/mL) (y-axis) and (Naive, Vehicle PO; and degrader I-30 PO TID: 10 mg/kg; 30 mg/kg; and 100 mg/kg) (x-axis).
• FIG.16 includes graphical images of comparative TLR-stimulated pro-inflammatory cytokine inhibition results in vitro using a degrader I-75 and IRAK4 inhibitor PF-06550833 for LPS (TLR4)-induced IL-6 (A), LPS (TLR4)-induced TNFa (B), R848 (TLR7/8)-induced IL-8 (C), and LPS (TLR4)-induced IL-1b (D) showing DMSO control (%) (y-axis) versus concentration (log ⁇ M) (x-axis) in human whole blood.
• FIG.17 includes graphical images of MSU induced gouty arthritis anti-inflammatory and analgesic results showing knee swelling (% control) (x-axis) and (Vehicle PO; colchicine SC; anakinra IP; and PO doses of degrader I-75: 10 mg/kg; 30 mg/kg; and 100 mg/kg) (x-axis) (A); and pain sensitivity (% control) (x-axis) and (Vehicle PO; colchicine SC; anakinra IP; and PO doses of degrader: 10 mg/kg; 30 mg/kg; and 100 mg/kg) (x-axis) (B).
• FIG. 18 is a graphical image of IRAK4 degradation in OCI-LY10 tumor xenograft without regression for vehicle (PO, BID) and degrader I-257 (PO, BID, 150 mg/kg), showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis).
• FIG.19 is a graphical image of viability results using PF-06650833, pomalidoamide, 1:1 PF-06650833:pomalidomide, and degrader I-387 showing viability (% control) (y-axis) versus concentration ( ⁇ M) (x-axis) for OCI-LY10 (MYD88 L265P, CD79 mutant) cells.
• FIG.20 includes transcriptome scatterplots of IFN signaling results showing -log 10 p- values of I-257, pomalidomide, and I-208 in DMSO (y-axis).
• FIG. 21 is a graphical image of IRAK4 and Ikaros degradation in OCI-LY10 tumor xenograft with regression for vehicle (PO, QD) and degrader I-208 (PO, QD; 24, 72, and 240 mg/kg), showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis).
• FIG.22 shows pharmacokinetic results of I-75 and I-241.
• FIG.23 is a graphical image of xenograph results for vehicle (SC, QD) and degrader I-38 and I-73 (SC, QD: 60 mg/kg) showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.24 is a graphical image of xenograph results for vehicle (SC, 5 ⁇ L/g, QD) and degrader I-3, I-11, I-62, I-110, I-113, and I-117 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.25 is a graphical image of xenograph results for vehicle (SC, 5 ⁇ L/g, QD) and degrader I-41, I-61, I-114, I-123, I-125, I-127, and I-241 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.26 is a graphical image of xenograph results for vehicle (PO, BID) and degrader I-125 and I-239 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.27 is a graphical image of xenograph results for vehicle (PO, QD) and degrader I-167 and I-259 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.28 is a graphical image of xenograph results for vehicle (PO, BID) and degrader I-168 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.29 is a graphical image of xenograph results for vehicle (PO, QD) and degrader I-221 (30 mg/kg, PO, QD) showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.30 is a graphical image of xenograph results for vehicle (SC, 5 ⁇ L/g, QD) and degrader I-168 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days after start of treatment) (x-axis) for OCI-LY10 (MYD88 mutant) cells.
• FIG.31 is a graphical image of xenograph results for vehicle (PO, BID) and degrader I-168 and I-208 at various dosing regimens showing tumor volume (mm 3 ) (y-axis) versus dosing interval (days post-randomization) (x-axis) for SUDHL-2 cells.
• FIG.32 is a graphical image depicting WBCs in exudate collected from air pouch in mouse following MSU crystal challenge using showing total cell count (% cells in extrudate) (y- axis) and (MSU; colchicine; 30, 100, and 300 mg/kg PO BID I-417; and 50 mg/kg PO BID I-257) (x-axis).
• FIG.33 is a graphical image depicting neutrophils in exudate collected from air pouch in mouse following MSU crystal challenge using showing total cell count (% cells in extrudate) (y-axis) and (MSU; colchicine; 30, 100, and 300 mg/kg PO BID I-417; and 50 mg/kg PO BID I- 257) (x-axis).
• FIG. 34 is a graphical image depicting IL-1b in exudate collected from air pouch in mouse following MSU crystal challenge using showing total cell count (% cells in extrudate) (y- axis) and (MSU; colchicine; 30, 100, and 300 mg/kg PO BID I-417; and 50 mg/kg PO BID I-257) (x-axis).
• FIG.35 includes graphical images depicting the effect of pretreatment with I-417 on exudate TNFa content showing average TNFa (pg) (y-axes) and MSU, colchicine, and 30, 100, and 300 mg/kg PO I-417 (x-axes).
• FIG. 36 is a graphical image depicting mouse imiquimod (IMQ) induced skin inflammation showing change in ear thicknesss ( ⁇ m) (y-axis) and vehicle, clobetasol, and I-417 (30, 100, and 300 mg/kg, PO, BID) (x-axis).
• IMQ mouse imiquimod
• FIG.37 includes graphical images depicting the results of the mouse intra peritoneal MSU induced peritonitis model showing lavage fluid IL-1b levels (left) and plasma IL-6 levels (right) (pg/mL) (y-axis) and naive, vehicle (PO), and 10, 30, and 100 mg/kg I-30 (PO TID) (x- axis).
• FIG.38 includes graphical images depicting the results of a PD study using I-417 in wild-type mice showing IRAK4 level (y-axis) over time (hr) (x-axis) in skin (left) and spleen (right).
• Compounds of the present invention, and compositions thereof, are useful as degraders and/or inhibitors of one or more IRAK protein kinases.
• a provided compound degrades and/or inhibits IRAK-1/2/3/4.
• the present invention provides a compound of formula I:
• IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4; L is a bivalent moiety that connects IRAK to LBM; and
• LBM is a ligase binding moiety.
• the present invention provides a compound of Formula V:
• IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4; L is a bivalent moiety that connects IRAK to DIM; and
• DIM is a degradation inducing moiety.
• aliphatic or“aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,”“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-6 aliphatic carbon atoms.
• aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
• “cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
• a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
• a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
• lower alkyl refers to a C 1-4 straight or branched alkyl group.
• exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
• lower haloalkyl refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
• heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
• alkylene refers to a bivalent alkyl group.
• An“alkylene chain” is a polymethylene group, i.e.,–(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• alkenylene refers to a bivalent alkenyl group.
• a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure: .
• halogen means F, Cl, Br, or I.
• aryl used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
• the term“aryl” may be used interchangeably with the term“aryl ring.”
• “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
• aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
• heteroaryl and“heteroar—,” used alone or as part of a larger moiety e.g., “heteroaralkyl,” or“heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• heteroaryl and“heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
• a heteroaryl group may be mono– or bicyclic.
• the term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted.
• the term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
• heterocycle “heterocyclyl,”“heterocyclyl ring,”“heterocyclic group,”“heterocyclic moiety,” and“heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
• a heterocyclyl group may be mono– or bicyclic.
• the term“heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
• the term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
• compounds of the invention may contain“optionally substituted” moieties.
• the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
• an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• the term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;–(CH2)0–4R ⁇ ;–(CH2)0–4OR ⁇ ; -O(CH2)0-4R o ,–O– (CH2)0–4C(O)OR°;–(CH2)0–4CH(OR ⁇ )2;–(CH2)0–4SR ⁇ ;–(CH2)0–4Ph, which may be substituted with R°;–(CH2)0–4O(CH2)0–1Ph which may be substituted with R°;
• –CH CHPh, which may be substituted with R°;
• (CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°;–NO2;–CN; –N 3 ; -(CH 2 ) 0–4 N(R ⁇ ) 2 ; –(CH 2 ) 0–4 N(R ⁇ )C(O)R
• Suitable monovalent substituents on R ⁇ are independently halogen,–(CH2)0–2R ⁇ , –(haloR ⁇ ),–(CH2)0–2OH,–(CH2)0–2OR ⁇ ,–(CH2)0–2CH(OR ⁇ )2; -O(haloR ⁇ ),–CN,–N3,–(CH2)0– 2C(O)R ⁇ ,–(CH2)0–2C(O)OH,–(CH2)0–2C(O)OR ⁇ ,–(CH2)0–2SR ⁇ ,–(CH2)0–2SH,–(CH2)0–2NH2,– (CH 2 ) 0–2 NHR ⁇ ,–(CH 2 ) 0–2 NR ⁇
• R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic,– CH 2 Ph,–O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include:–O(CR *
• R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen,–R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ ,–O(haloR ⁇ ),–CN,–C(O)OH,–C(O)OR ⁇ ,–NH 2 ,–NHR ⁇ ,–NR ⁇
• each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic,–CH2Ph,–O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include –R ⁇ , –NR ⁇
• each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted–OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen,– R ⁇ , -(haloR ⁇ ),–OH,–OR ⁇ ,–O(haloR ⁇ ),–CN,–C(O)OH,–C(O)OR ⁇ ,–NH2,–NHR ⁇ ,–NR ⁇
• each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic,–CH 2 Ph,–O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• the term“provided compound” refers to any genus, subgenus, and/or species set forth 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.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• 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.
• 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, pec
• 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, loweralkyl sulfonate and aryl sulfonate.
• 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.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention
• an inhibitor is defined as a compound that binds to and /or inhibits an IRAK kinase with measurable affinity.
• 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.
• a 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 ubiqitination and subsequent degradation of the IRAK kinase.
• a degrader has an DC 50 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.
• the term “monovalent” refers to a degrader compound without an appended E3 ligase binding moiety.
• a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
• a detectable moiety may be attached to a provided compound via a suitable substituent.
• suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
• moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
• moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain.
• such moieties may be attached via click chemistry.
• such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
• Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed.2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.
• the term“detectable moiety” is used interchangeably with the term "label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
• Primary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
• Detectable moieties also include luminescent and phosphorescent groups.
• secondary label refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
• the secondary intermediate may include streptavidin-enzyme conjugates.
• antigen labels secondary intermediates may include antibody-enzyme conjugates.
• fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
• fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
• mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
• mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
• mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
• nucleotides dideoxynucleotides
• oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
• other synthetic polymers of varying length and monomer composition.
• a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
• 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.
• the present invention provides a compound of formula I:
• IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4; L is a bivalent moiety that connects IRAK to LBM; and
• LBM is a ligase binding moiety.
• the present invention provides a compound of formula I:
• IRAK is an IRAK-4 binding moiety
• L is a bivalent moiety that connects IRAK to LBM
• LBM is a cereblon ligase binding moiety.
• the present invention provides a compound of formula V:
• IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4; L is a bivalent moiety that connects IRAK to DIM; and
• DIM is a degradation inducing moiety.
• the present invention provides a compound of formula V:
• IRAK is an IRAK-4 binding moiety
• L is a bivalent moiety that connects IRAK to DIM
• DIM is LBM, a lysine mimetic, or a hydrogen atom.
• IRAK Binding Moeity IRAK
• the present invention provides a compound of formula I, where IRAK is a IRAK-4 binding moiety thereby forming a compound of formula II:
• L and LBM are as defined above and described in embodiments herein, and wherein:
• Ring A is a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring B is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring C is phenyl or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 1 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, - CF 2 (R), -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, or -C(O)NR 2 ;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR 2
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 3 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -S(O)(NR)R , -P(O)(OR) 2, -P(O)(NR 2 ) 2, -CF 2 (R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R; each R 5 is independently an optionally substituted group selected from C1-6
• each n is 0, 1, or 2;
• each m is 0, 1, 2, 3 or 4;
• each p is 0, 1, 2, 3 or 4;
• the present invention provides a compound of Formula II ⁇ :
• Ring A is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring B is phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring C is phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -S(O)(NR)R , -P(O)(OR) 2, -P(O)(NR 2 ) 2, -CF 2 (R), - CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, - C(O)
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 5 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each n is 0, 1, or 2;
• each m is 0, 1, 2, 3 or 4;
• each p is 0, 1, 2, 3 or 4;
• the present invention provides a compound of formula V, where IRAK is a IRAK-4 binding moiety thereby forming a compound of formula V-a:
• Ring A is a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring B is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring C is phenyl or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 1 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, - CF 2 (R), -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, or -C(O)NR 2 ;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR 2
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 3 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -S(O)(NR)R , -P(O)(OR) 2, -P(O)(NR 2 ) 2, -CF 2 (R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R; each R 5 is independently an optionally substituted group selected from C1-6
• each n is 0, 1, or 2;
• each m is 0, 1, 2, 3 or 4;
• each p is 0, 1, 2, 3 or 4;
• Ring A is a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring A is cyclobutyl. In some embodiments, Ring A is cyclopentyl. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is cycloheptyl. In some embodiments, Ring A is . In some embodiments, Ring A is .
• Ring A is selected from those depicted in Table 1, below.
• Ring B is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring B is phenyl. In some embodiments, Ring B is a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00105] In some embodiments, Ring B is . In some embodiments, Ring B is
• Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is
• Ring C is phenyl or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring C is phenyl. In some embodiments, Ring C is a 5-10 membered mono- or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring C is . In some embodiments, Ring C is
• Ring C is . In some embodiments, Ring C
• Ring C is . In some embodiments, Ring
• Ring C is . In some embodiments, Ring C is . In some embodiments,
• Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is .
• Ring C is . In some embodiments, Ring C is
• Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . [00110] In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is .
• Ring C is selected from those depicted in Table 1, below.
• L 2 a covalent bond.
• L 2 is a C1-3 aliphatic.
• L 2 is–CH 2 –.
• L 2 is–C(D)(H)-.
• L 2 is -C(D) 2 –. In some embodiments, L 2 is–CH 2 CH 2 –. In some embodiments, L 2 is–NR–. In some embodiments, L 2 is–CH2NR–. In some embodiments, L 2 is or–O–. In some embodiments, L 2 is –CH2O–. In some embodiments, L 2 is–S–. In some embodiments, L 2 is -OC(O)-. In some embodiments, L 2 is -C(O)O-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is - S(O)-. In some embodiments, L 2 is -S(O)2-,.
• L 2 is -NRS(O)2-. In some embodiments, L 2 is -S(O)2NR-. In some embodiments, L 2 is -NRC(O)-. In some embodiments, L 2 is -C(O)NR-. In some embodiments, L 2 is -OC(O)NR-. In some embodiments, L 2 is– NRC(O)O-.
• L 3 is a C1-3 aliphatic.
• L 3 is–CH2–.
• L 3 is–C(D)(H)-.
• L 3 is -C(D) 2 –.
• L 3 is–CH2CH2–. In some embodiments, L 3 is–NR–. In some embodiments, L 3 is–CH2NR–. In some embodiments, L 3 is or–O–. In some embodiments, L 3 is–CH 2 O–. In some embodiments, L 3 is–S–. In some embodiments, L 3 is -OC(O)-. In some embodiments, L 3 is -C(O)O-. In some embodiments, L 3 is -C(O)-. In some embodiments, L 3 is -S(O)-. In some embodiments, L 3 is - S(O) 2 -,. In some embodiments, L 3 is -NRS(O) 2 -.
• L 3 is -S(O) 2 NR-. In some embodiments, L 3 is -NRC(O)-. In some embodiments, L 3 is -C(O)NR-. In some embodiments, L 3 is -OC(O)NR-. In some embodiments, L 3 is–NRC(O)O-.
• L 2 and L 3 are selected from those depicted in Table 1, below.
• each R 1 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), -CFR2, - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)OR, -N(R)C(O)OR, -N(R)C(O)OR, -N(R)C(O)OR, -N(
• each R 1 is independently hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, each R 1 is independently–R 5 . In some embodiments, each R 1 is independently halogen. In some embodiments, each R 1 is independently–CN. In some embodiments, each R 1 is independently -NO 2 . In some embodiments, each R 1 is independently– OR. In some embodiments, each R 1 is independently–SR. In some embodiments, each R 1 is independently -NR2. In some embodiments, each R 1 is independently -S(O)2R. In some embodiments, each R 1 is independently -S(O) 2 NR 2. In some embodiments, each R 1 is independently -S(O)R.
• each R 1 is independently -S(O)(NR)R. In some embodiments, each R 1 is independently -P(O)(OR)2. In some embodiments, each R 1 is independently -P(O)(NR 2 ) 2 . In some embodiments, each R 1 is independently -CF 2 (R). In some embodiments, each R 1 is independently -CFR 2 . In some embodiments, each R 1 is independently - CF3. In some embodiments, each R 1 is independently -CR2(OR). In some embodiments, each R 1 is independently -CR2(NR2). In some embodiments, each R 1 is independently -C(O)R. In some embodiments each R 1 is independently -C(O)OR.
• each R 1 is independently -C(O)NR2. In some embodiments, each R 1 is independently -C(O)N(R)OR. In some embodiments, each R 1 is independently -OC(O)R. In some embodiments, each R 1 is independently -OC(O)NR 2 . In some embodiments, each R 1 is independently -N(R)C(O)OR. In some embodiments, each R 1 is independently -N(R)C(O)R. In some embodiments, each R 1 is independently -N(R)C(O)NR2. In some embodiments, each R 1 is independently -N(R)S(O)2R. In some embodiments, each R 1 is independently -N + (O-)R 2 .
• each R 1 is independently -OP(O)R 2 . In some embodiments, each R 1 is independently -OP(O)(OR) 2 . In some embodiments, each R 1 is independently -OP(O)(OR)NR2. In some embodiments, each R 1 is independently -OP(O)(NR2)2. In some embodiments, each R 1 is independently -P(O)R2. In some embodiments, each R 1 is independently -SiR 3 . In some embodiments, each R 1 is independently - Si(OR)R2. In some embodiments, each R 1 is independently -SF5. In some embodiments, each R 1
• R 1 is -CHF 2 . In some embodiments, R 1 is -C(OH)(CH 3 ) 2 . In some embodiments, R 1 is -C(O)NH 2 . In some embodiments, R 1 is -CF 3 . In some embodiments, R 1 is -iPr. In some embodiments, R 1 is isoprene. In some embodiments, R 1 is . In some embodiments, R 1 is N .
• each R 2 and R 3 are independently hydrogen, deuterium, - R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), -CFR2, - CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -
• each R 2 and R 3 are independently hydrogen. In some embodiments, each R 2 and R 3 are independently deuterium. In some embodiments, each R 2 and R 3 are independently–R 5 . In some embodiments, each R 2 and R 3 are independently halogen. In some embodiments, each R 2 and R 3 are independently–CN. In some embodiments, each R 2 and R 3 are independently -NO2. In some embodiments, each R 2 and R 3 are independently–OR. In some embodiments, each R 2 and R 3 are independently–SR. In some embodiments, each R 2 and R 3 are independently -NR 2 . In some embodiments, each R 2 and R 3 are independently -S(O) 2 R.
• each R 2 and R 3 are independently -S(O)2NR2. In some embodiments, each R 2 and R 3 are independently -S(O)R. In some embodiments, each R 2 and R 3 are independently -S(O)(NR)R. In some embodiments, each R 2 and R 3 are independently -P(O)(OR) 2 . In some embodiments, each R 2 and R 3 are independently -P(O)(NR2)2. In some embodiments, each R 2 and R 3 are independently -CF2(R). In some embodiments, each R 2 and R 3 are independently -CFR 2 . In some embodiments, each R 2 and R 3 are independently -CF 3 .
• each R 2 and R 3 are independently -CR2(OR). In some embodiments, each R 2 and R 3 are independently -CR2(NR2). In some embodiments, each R 2 and R 3 are independently -C(O)R. In some embodiments, each R 2 and R 3 are independently -C(O)OR. In some embodiments, each R 2 and R 3 are independently -C(O)NR 2 . In some embodiments, each R 2 and R 3 are independently -C(O)N(R)OR. In some embodiments, each R 2 and R 3 are independently -OC(O)R. In some embodiments, each R 2 and R 3 are independently -OC(O)NR 2 .
• each R 2 and R 3 are independently -N(R)C(O)OR. In some embodiments, each R 2 and R 3 are independently -N(R)C(O)R. In some embodiments, each R 2 and R 3 are independently -N(R)C(O)NR2. In some embodiments, each R 1 and R 2 are independently - N(R)S(O) 2 R. In some embodiments, each R 2 and R 3 are independently -N + (O-)R 2 . In some embodiments, each R 2 and R 3 are independently -OP(O)R2. In some embodiments, each R 2 and R 3 are independently -OP(O)(OR)2.
• each R 2 and R 3 are independently - OP(O)(OR)NR 2 . In some embodiments, each R 2 and R 3 are independently -OP(O)(NR 2 ) 2 . In some embodiments, each R 2 and R 3 are independently -P(O)R2. In some embodiments, each R 2 and R 3 are independently -SiR3. In some embodiments, each R 2 and R 3 are independently - Si(OR)R 2 . In some embodiments, each R 2 and R 3 are independently -SF 5 . In some embodiments,
• each R 2 and R 3 are independently .
• R 2 is–CF 3 .
• R 2 is .
• R 2 is .
• R 2 is .
• R 2 is -C(OH)(CH 3 ) 2 .
• R 2 is .
• R 3 is -NHCH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is . In some embodiments, R 3 is . In some embodiments, R 3 is -C(OH)(CH 3 ) 2 . In some embodiments, R 3 is .
• each R 1 , R 2 , and R 3 are independently selected from those depicted in Table 1, below.
• R 4 is selected from , hydrogen, or an optionally substituted group selected from C1-6 aliphatic or a 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, or spiro ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 4 is .
• R 4 is hydrogen.
• R 4 is an optionally substituted group selected from C 1-6 aliphatic.
• R 4 is an optionally substituted 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, or spiro ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In
• R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some
• R 4 is . In some embodiments, R 4 is . In some
• R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is
• R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is
• R 4 is . In some embodiments, R 4 is . In some
• R 4 is . In some embodiments, R 4 is . In some
• R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring D is phenyl. In some embodiments, Ring D is a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring D is . In some embodiments, Ring D is
• Ring D is . In some embodiments, Ring D is
• Ring D is . In some embodiments, Ring D is
• Ring D is . In some embodiments, Ring D is
• Ring D is selected from those depicted in Table 1, below.
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.
• each R is independently hydrogen. In some embodiments, each R is an optionally substituted group selected from C 1-6 aliphatic. In some embodiments, each R is an optionally substituted phenyl. In some embodiments, each R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• two R groups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.
• each R is selected from those depicted in Table 1, below.
• each R 5 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each R 5 is independently an optionally substituted group selected from C 1-6 aliphatic. In some embodiments, each R 5 is independently an optionally substituted phenyl. In some embodiments, each R 5 is independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R 5 is independently an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00137] . In some embodiments, R 5 is optionally substituted .
• each R 5 is selected from those depicted in Table 1, below.
• each n is independently 0, 1, or 2.
• each n is independently 0. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2.
• each m and p are independently 0, 1, 2, 3 or 4.
• each m and p are independently 0. In some embodiments, each m and p are independently 1. In some embodiments, each m and p are independently 2. In some embodiments, each m and p are independently 3. In some embodiments, each m and p are independently 4.
• each m and p are selected from those depicted in Table 1, below.
• the present invention provides the compound of formula II, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, and L 3 is a covalent bond thereby forming a compound of formula II-a:
• each of LBM, L, R 1 , R 2 , R 3 , Ring C, Ring D, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula II, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring C is oxazolyl, and L 3 is a covalent bond thereby forming a compound of formula II-b:
• each of LBM, L, R 1 , R 2 , R 3 , Ring D, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula II, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring D is pyridyl, and L 3 is a covalent bond thereby forming a compound of formula II-c:
• each of LBM, L, R 1 , R 2 , R 3 , Ring C, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula II, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, thereby forming a compound of formula II-d:
• each of LBM, L, L 3 , R1, R 2 , R 4 , Ring C, n, and m is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula II-d:
• L and LBM are as defined above and described in embodiments herein, and wherein:
• Ring C is phenyl or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -S(O)(NR)R , -P(O)(OR) 2, -P(O)(NR 2 ) 2, -CF 2 (R), - CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, - C(O)
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 3 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• each R 5 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each n is 0, 1, or 2;
• each m is 0, 1, 2, 3 or 4;
• each p is 0, 1, 2, 3 or 4.
• the present invention provides the compound of formula II, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring C is pyrazolo[1,5-a]pyrimidyl, thereby forming a compound of formula II-e:
• each of LBM, L, L 3 , R1, R 2 , R 4 , n, and m is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula II-e:
• L and LBM are as defined above and described in embodiments herein, and wherein:
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO2, -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -S(O)(NR)R , -P(O)(OR) 2, -P(O)(NR 2 ) 2, -CF 2 (R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(
• Ring D is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 3 is independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), - CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• each R 5 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each n is 0, 1, or 2;
• each m is 0, 1, 2, 3 or 4;
• each p is 0, 1, 2, 3 or 4.
• the present invention provides the compound of formula V-a, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, and L 3 is a covalent bond thereby forming a compound of formula V-b:
• each of DIM, L, R 1 , R 2 , R 3 , Ring C, Ring D, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula V-a, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring C is oxazolyl, and L 3 is a covalent bond thereby forming a compound of formula V-c:
• each of DIM, L, R 1 , R 2 , R 3 , Ring D, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula V-a, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring D is pyridyl, and L 3 is a covalent bond thereby forming a compound of formula V-d:
• each of DIM, L, R 1 , R 2 , R 3 , Ring C, n, m, and p is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula V-a, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, L 3 is a covalent bond, and R 4 is hydrogen thereby forming a compound of formula V-e:
• each of DIM, L, L 3 , R 1 , R 2 , R 4 , Ring C, n, and m is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula V-a, wherein Ring A is cyclohexyl, Ring B is pyrazolyl, Ring C is pyrazolo[1,5-a]pyrimidyl, L 3 is a covalent bond, and R 4 is hydrogen thereby forming a compound of formula V-f:
• each of DIM, L, L 3 , R 1 , R 2 , R 4 , n, and m is as defined above and described in embodiments herein, both singly and in combination.
• IRAK is . In some embodiments, IRAk is . In some embodiments, IRAK is . In some embodiments, IRAK is IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments,
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is .
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is .
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is H N O O N N N N N F
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is IRAK is IRAK is IRAK is
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is .
• the present invention provides a compound of formula I, where IRAK is a IRAK-4 binding moiety thereby forming a compound of formula III:
• L and LBM are as defined above and described in embodiments herein, and wherein:
• Ring A is a 4-7 membered saturated monocyclic ring having two ring nitrogen atoms
• Ring B is a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring C is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 1 is independently hydrogen, deuterium, -R 4 , halogen, -CN, -NO2, -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -CF 2 (R), -CF 3 , -CR 2 (OR), - CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
• each R 4 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each n is 0, 1, 2, 3 or 4;
• the compound of formula III is not compound I-101, I-102, I-103, I-104, or I-105 in Table 1A.
• the present invention provides a compound of formula V, where IRAK is a IRAK-4 binding moiety thereby forming a compound of formula V-g:
• Ring A is a 4-7 membered saturated monocyclic ring having two ring nitrogen atoms
• Ring B is a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring C is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R 1 is independently hydrogen, deuterium, -R 4 , halogen, -CN, -NO 2 , -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -CF 2 (R), -CF 3 , -CR 2 (OR), - CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R;
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
• each R 4 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each n is 0, 1, 2, 3 or 4;
• the compound of formula V-g is not compound I-101, I-102, I-103, I-104, or I-105 in Table 1A.
• Ring A is a 4-7 membered saturated monocyclic ring having two ring nitrogen atoms.
• Ring A is piperazine. In some embodiments, Ring A is 1,4- diazepane.
• Ring A is selected from those depicted in Table 1, below.
• Ring B a 4-10 membered saturated mono- or bicyclic carbocyclic or hetereocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring B is cyclobutyl.
• Ring B is cyclopentyl.
• Ring B is cyclohexyl.
• Ring B is cycloheptyl.
• Ring B is selected from those depicted in Table 1, below.
• Ring C is a 9 membered bicyclic heteroaryl ring having 1- 3 nitrogen atoms.
• Ring C is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring B is phenyl. In some embodiments, Ring is a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring In some embodiments, Ring C is
• Ring some embodiments, Ring C is
• Ring some embodiments, Ring C is
• Ring C is . In some embodiments, Ring C is
• Ring C is selected from those depicted in Table 1, below.
• L 2 a covalent bond.
• L 2 is a C1-3 aliphatic.
• L 2 is–CH 2 –.
• L 2 is–C(D)(H)-.
• L 2 is -C(D) 2 –. In some embodiments, L 2 is–CH 2 CH 2 –. In some embodiments, L 2 is–NR–. In some embodiments, L 2 is–CH2NR–. In some embodiments, L 2 is or–O–. In some embodiments, L 2 is –CH2O–. In some embodiments, L 2 is–S–. In some embodiments, L 2 is -OC(O)-. In some embodiments, L 2 is -C(O)O-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is - S(O)-. In some embodiments, L 2 is -S(O)2-,.
• L 2 is -NRS(O)2-. In some embodiments, L 2 is -S(O)2NR-. In some embodiments, L 2 is -NRC(O)-. In some embodiments, L 2 is -C(O)NR-. In some embodiments, L 2 is -OC(O)NR-. In some embodiments, L 2 is– NRC(O)O-.
• L 2 is selected from those depicted in Table 1, below.
• each R 1 is independently hydrogen, -R 4 , halogen, -CN, - NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -CF 2 (R), -CR 2 (CN), -CF 3 , -CR 2 (OR), - CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R.
• each R 1 is independently hydrogen. In some embodiments, each R 1 is independently -R 4 . In some embodiments, each R 1 is independently halogen. In some embodiments, each R 1 is independently–CN. In some embodiments, each R 1 is independently - NO 2 . In some embodiments, each R 1 is independently–OR. In some embodiments, each R 1 is independently–SR. In some embodiments, each R 1 is independently -NR2. In some embodiments, each R 1 is independently -S(O) 2 R. In some embodiments, each R 1 is independently -S(O) 2 NR 2. In some embodiments, each R 1 is independently -S(O)R. In some embodiments, each R 1 is independently -CF2(R).
• each R 1 is independently -CR2(CN). In some embodiments, each R 1 is independently -CF3. In some embodiments, each R 1 is independently - CR 2 (OR). In some embodiments, each R 1 is independently -CR 2 (NR 2 ). In some embodiments, each R 1 is independently -C(O)R. In some embodiments, each R 1 is independently -C(O)OR. In some embodiments, each R 1 is independently -C(O)NR2. In some embodiments, each R 1 is independently -C(O)NR 2 . In some embodiments, each R 1 is independently -C(O)N(R)OR. In some embodiments, each R 1 is independently -OC(O)R.
• each R 1 is independently -OC(O)NR2. In some embodiments, each R 1 is independently -N(R)C(O)OR. In some embodiments, each R 1 is independently -N(R)C(O)R. In some embodiments, each R 1 is independently -N(R)C(O)NR 2 . In some embodiments, each R 1 is independently -N(R)S(O) 2 R.
• R 1 N N R 1 N N
• R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiment, R 1 is methyl. In some embodiments, R 1 is -CH 2 (CN). In some embodiments, R 1 is -CN.
• each R 1 is independently selected from those depicted in Table 1, below.
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• each R is independently hydrogen.
• each R is an optionally substituted group selected from C 1-6 aliphatic. In some embodiments, each R is a phenyl. In some embodiments, each R is a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• each R is selected from those depicted in Table 1, below.
• each R 4 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each R 4 is independently an optionally substituted group selected from C1-6 aliphatic. In some embodiments, each R 4 is independently an optionally substituted phenyl. In some embodiments, each R 4 is independently an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R 4 is independently an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each R 4 is selected from those depicted in Table 1, below.
• each n is independently 0, 1, or 2.
• each n is independently 0. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2.
• each n is selected from those depicted in Table 1, below.
• the present invention provides the compound of formula III, wherein Ring B is cyclohexyl thereby forming a compound of formula III-a:
• the invention provides the compound of formula III, wherein L 2 is a covalent bond, Ring B is cyclohexyl, and Ring C is pyrrolo[2,1-f][1,2,4]triazinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, or quinazolinyl thereby forming a compound of formula III-b, III-c, or III-d respectively:
• each of LBM, L, Ring A, R 1 , and n is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides the compound of formula V-g, wherein Ring B is cyclohexyl thereby a compound of formula V-h:
• each of DIM, L, L 2 , Ring A, R 1 , Ring C, and n is as defined above and described in embodiments herein, both singly and in combination.
• the invention provides the compound of formula V-g, wherein L 2 is a covalent bond, Ring B is cyclohexyl, and Ring C is pyrrolo[2,1-f][1,2,4]triazinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, or quinazolinyl thereby forming a compound of formula V-i-1, V-i-2, or V-i-3 respectively:
• each of DIM, L, Ring A, R 1 , and n is as defined above and described in embodiments herein, both singly and in combination.
• IRAK is . In some embodiments,
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is . In some embodiments,
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
• IRAK is selected from those in Table 1, below.
• the present invention provides a compound of Formula I,
• IRAK is an IRAK-4 inhibitor ; thereby forming a compound of formula IV:
• IRAK is . In some embodiments,
• IRAK is . In some embodiments, IRAK is
• IRAK is In some embodiments,
• IRAK is . In some embodiments, IRAK is . In some embodiments, IRAK is
• IRAK is . In some embodiments,
• IRAK is . In some embodiments, IRAK is
• IRAK is .
• IRAK is .
• IRAK is selected from those in Table 1, below.
• Ligase Binding Moiety (LBM) LBM
• LBM is an E3 ligase ligand.
• E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T. Uehara et al.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• Y is a bond, Y1, O, NH, NR2, C(O)O, OC(O), C(O)NR2 , NR2 C(O), Y1-O, Y1-NH, Y1-NR2, Y1- C(O), Y1-C(O)O, Y1-OC(O), Y1-C(O)NR2 , or Y1-NR2 C(O), wherein Y1 is C1-6 alkylene, C 2 - 6 alkenylene, or C 2 -C 6 alkynylene;
• X is C(O) or C(R 3 ) 2 ;
• X1-X2 is C(R3) ⁇ N or C(R3)2—C(R3)2;
• each R 1 is independently halogen, nitro, NH 2 , OH, C(O)OH, C 1 - 6 alkyl, or C 1 - 6 alkoxy;
• R 2 is C 1 - 6 alkyl, C 2 - 6 alkenyl, C 3 - 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)-C 1 - 6 alkyl, C(O)-C2-6 alkenyl, C(O)-C3-8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R 2 is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 - 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 - 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6- 10 aryl or 5- to 10-membered heteroaryl
• R2 is H, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and R2, when not being H, is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 - 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 - 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C3-8 cycloalkyl, 3- to 8- membered heterocycloalkyl, C 6 - 10 aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 - 6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or
• each R3 is independently H or C1-3 alkyl optionally substituted with C6-10 aryl or 5- to 10- membered heteroaryl;
• each R3 is independently C1-3 alkyl
• each R4 is independently H or C1-3 alkyl; or two R4, together with the carbon atom to which they are attached, form C(O), a C 3 - 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
• R5 is H, C1-3 alkyl, F, or Cl; each Ra independently is H or C1-6 alkyl;
• R b is H or tosyl
• t is 0 or 1;
• n 0, 1, 2 or 3;
• n 0, 1 or 2
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• the present invention provides a compound of formula I,
• LBM is a VHL E3 ubiquitin ligase binding moiety , thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, or I-b-5 respectively:
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–,
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of formula I,
• LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen, –CN, –NO 2 ,–OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring A is a bi- or tricyclic ring selected from , ,
• Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R) 2 , or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formala I-c ⁇ above is provided as a compound of formula I-c ⁇ or formula I-c ⁇ :
• each of IRAK, Ring A, L, R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1a is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–N(R) 2 , -Si(R) 3 , or an optionally substituted C 1-4 aliphatic;
• each R 2a is independently hydrogen, deuterium,–R 6a , halogen,–CN,–NO2,–OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring A a is a bi- or tricyclic ring selected from
• Ring B a is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3a is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4a is independently hydrogen, –R 6a , halogen, –CN, –NO2, –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5a is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6a is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formala I-c-1 above is provided as a compound of formula I-c-1 ⁇ or formula I-c-1 ⁇ :
• each of IRAK, Ring A a , L, R 1a , R 2a , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, or ;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O)2R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO2,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen, –CN, –NO2,–OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• the compound of formala I-d ⁇ above is provided as a compound of formula I-d ⁇ or formula I-d ⁇ :
• each of IRAK, Ring A, Ring B, L, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , m, and p is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1b is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2b is independently hydrogen, deuterium,–R 6b , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• Ring B b is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3b and R 4b is independently hydrogen,–R 6 , halogen,–CN,–NO2,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5b is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6b is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring A b and Ring B b is connected to
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formala I-d-1 above is provided as a compound of formula I-d-1 ⁇ or formula I-d-1 ⁇ :
• each of IRAK, Ring A b , Ring B b , L, R 1b , R 2b , R 3b , X 1 , X 2 , X 3 , m, and p is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–NR2, or an optionally substituted C1-4 aliphatic;
• Ring A is a mono- or bicyclic ring selected from , ,
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen, –CN, –NO 2 ,–OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formala I-e ⁇ above is provided as a compound of formula I-e ⁇ or formula I-e ⁇ :
• each of IRAK, Ring A, Ring B, L, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , p, and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–,
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1c is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2c is independently hydrogen, deuterium,–R 6c , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring B c is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3c and R 4c is independently hydrogen,–R 6c , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5c is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6c is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formala I-e-1 above is provided as a compound of formula I-e-1 ⁇ or formula I-e-1 ⁇ :
• each of IRAK, Ring A c , Ring B c , L, R 1c , R 2c , R 3c , X 1 , X 2 , X 3 , p, and m is as defined above.
• the present invention provides a compound of formula I,
• LBM is a VHL E3 ubiquitin ligase binding moiety , , , , or thereby forming a compound of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5 or I-f-6 respectively:
• L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R 1’ , R 2’ , R 3’ , R5, R6, R7, R9, R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X’, Y, Z 1 , Z 2 , Z 3 , Z 4 , and o is as defined and described in WO 2016/149668 and US 2016/0272639, the entirety of each of which is herein incorporated by reference.
• LBM is VHL E3 ubiquitin ligase binding moiety
• R 1 ⁇ is an optionally substituted C1-6 alkyl group, an optionally substituted -(CH2)nOH, an optionally substituted -(CH 2 ) n SH, an optionally substituted (CH 2 ) n -O-(C 1 -C 6 )alkyl group, an optionally substituted (CH 2 ) n -WCOCW-(C 0 - 6 ) alkyl group containing an epoxide moiety WCOCW where each W is independently H or a C1-3 alkyl group, an optionally substituted -(CH 2 ) n COOH, an optionally substituted -(CH 2 ) n C(O)-(C 1 - 6 alkyl), an optionally substituted -(CH 2 ) n NHC(O)-R 1 , an optionally substituted -(CH 2 ) n C(O)-NR 1 R 2 , an optionally substituted -(CH2)nOC(O)-NR1R2, -(CH
• R1 and R2 are each independently H or a C1-6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups;
• R S is a C 1 - 6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a - (CH2)mNR1R2 group;
• X and X are each independently C ⁇ O, C ⁇ S, -S(O), S(O)2;
• R is an optionally substituted -(CH 2 ) n -(C ⁇ O) u (NR 1 ) v (SO 2 ) w alkyl group, an optionally substituted -(CH2)n-(C ⁇ O)u(NR1)v(SO2)wNR1NR2N group, an optionally substituted -(CH2)n- (C ⁇ O)u(NR1)v(SO2)w-Aryl, an optionally substituted -(CH2)n-(C ⁇ O)u(NR1)v(SO2)w- heteroaryl, an optionally substituted -(CH 2 ) n -(C ⁇ O) v NR 1 (SO 2 ) w -heterocycle, an optionally substituted -NR 1 -(CH2)n-C(O)u(NR1)v(SO2)w-alkyl, an optionally substituted -NR 1 -(CH2)n- C(O)u(NR1)v(SO2)w-NR1NR2N, an optionally substituted
• R 3 ⁇ is an optionally substituted alkyl, an optionally substituted -(CH2)n-(O)u(NR1)v(SO2)w-alkyl, an optionally substituted -(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N, an optionally substituted - (CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N, an optionally substituted -(CH2)n- C(O) u (NR 1 ) v (SO 2 ) w -C(O)NR 1 R 2 , an optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w - Aryl, an optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -heteroaryl, an optionally substituted -(CH2)n-C(O
• R1 is the same as above;
• R 1 and R1 ⁇ are each independently H or a C1-C3 alkyl group
• X R2 ⁇ and X R3 ⁇ are each independently an optionally substituted -CH 2 ) n -, -CH 2 ) n -CH(X v ) ⁇ CH(X v )-, -CH2)n-CHoCH-, -(CH2CH2O)n- or a C3-C6 cycloalkyl group, where Xv is H, a halo or a C1-C3 alkyl group which is optionally substituted; each m is independently 0, 1, 2, 3, 4, 5, 6;
• each m is independently 0 or 1;
• each n is independently 0, 1, 2, 3, 4, 5, 6;
• each n is independently 0 or 1;
• each u is independently 0 or 1;
• each v is independently 0 or 1;
• each w is independently 0 or 1.
• brackets around any LBM means that the moiety is covalently attached to said LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom.
• available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structure are depicted below, wherein each wavy bond defines the point of attachment to said
• the present invention provides a compound of formula I,
• LBM is a VHL E3 ubiquitin ligase binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R p , R 9 , R 10 , R 11 , R 14a , R 14b , R15, R16, W 3 , W 4 , W 5 , X 1 , X 2 , and o is as defined and described in WO 2017/030814, WO 2016/118666 and US 2016/0214972, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables A, G, G’, Q 1 , Q 2 , Q 3 , Q 4 , R, R’, W, X, Z, and n is as defined and described in WO 2016/197114 and US 2018/0147202, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3 ligase binding moiety
• LBM is a MDM2 E3 ligase binding moiety
• R1 and R2 are independently selected from the group consisting of an aryl or heteroaryl group, a heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group can be mono-cyclic or bi-cyclic, or unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, -CN, C1-6 alkyl group, C3-6 cycloalkyl, -OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1-6 carbons, sulfoxide with 1-6 carbons, sulfone with 1-6 carbons, ketone with 2-6 carbons, amides with 2-6 carbons, and dialkyl amine with 2-6 carbons;
• R11 is -C(O)-N(R h )(R i ), wherein R h and R i are selected from groups consisting of the following: H, C1 to C6 alkyl, alkoxy substituted alkyl, sulfone substituted alkyl, aryl, heterol aryl, mono- , bis- or tri-substituted aryl or hetero aryl, alkyl carboxylic acid, heteroaryl carboxylic acid, alkyl carboxylic acid, fluorine substituted alkyl carboxylic acid, aryl substituted cycloalkyl, hetero aryl substituted cycloalkyl; wherein R h and R i are independently selected from the group consisting of H, connected to form a ring, 4-hydroxycyclohehexane; mono- and di- hydroxy substituted alkyl (C3-6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid, and substituted phenyl-4-carboxy
• R 14 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
• R 15 is CN;
• R 12 is selected from the group consisting of alkyl, aryl substituted alkyl, alkoxy substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy substituted cycloalkyl,
• the present invention provides a compound of formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety selected from the group
• the present invention provides a compound of formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety selected from the group
• L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables A 1 , A 2 , A 3 , R 5 , G and Z is as defined and described in WO 2017/176958, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety , or ; thereby forming a compound of formula I-k-1, I-k-2, I-k-3, or I-k-4 respectively:
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• R 1 is selected from hydrogen or alkyl
• R 2 is selected from hydrogen or alkyl
• R 3 is selected from hydrogen, alkyl, cycloalkyl and heterocycloalkyl
• R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or
• R 5 and R 6 are taken together to form a pyrrolidine or a piperidine ring further optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which can then be further fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, or
• R 3 and R 5 are taken together to form a 5-8-membered ring further optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
• R 7 is selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each one further optionally substituted with 1-3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or R 7 is C(O)NHR 4 ; and
• R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, further optionally substituted with 1-3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or R 7 is C(O)NHR 4 ,
• the present invention provides a compound of formula I,
• L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 , is as defined and described in WO 2017/011590 and US 2017/0037004, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, ;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring A is a bi- or tricyclic ring selected from , ,
• Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, 2, 3 or 4;
• each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• Ring B Where a point of attachment of–(R 2 ) n is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of–(R 2 ) n may be on Ring A and may also be at any available carbon or nitrogen atom on Ring A including the ring to which Ring B is fused. Where -R 2 is attached to a nitrogen atom bound to R 4 or R 5 , R 4 or R 5 is absent and -R 2 takes the place of the R 4 or R 5 group. Where -R 2 is attached to a carbon atom bound to R 3 , R 3 is absent and -R 2 takes the place of the R 3 group.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–N(R) 2 , -Si(R) 3 , or an optionally substituted C 1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O)2R;
• Ring A is a bi- or tricyclic ring selected from ,
• Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, 2, 3 or 4;
• each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formala I-l ⁇ above is provided as a compound of formula I-l ⁇ or formula I-l ⁇ :
• each of IRAK, Ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1a is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2a is independently hydrogen, –R 6a , halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• Ring A a is a bi- or tricyclic ring selected from
• Ring B a is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3a is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4a is independently hydrogen, –R 6a , halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5a is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6a is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, 2, 3 or 4;
• each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• Ring B Where a point of attachment of–(R 2a )n is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of–(R 2a ) n may be on Ring A and may also be at any available carbon or nitrogen atom on Ring A including the ring to which Ring B is fused. Where -R 2a is attached to a nitrogen atom bound to R 4a or R 5a , R 4a or R 5a is absent and -R 2a takes the place of the R 4a or R 5a group. Where -R 2a is attached to a carbon atom bound to R 3a , R 3a is absent and -R 2a takes the place of the R 3a group.
• a compound of formala I-l-1 above is provided as a compound of formula I-l-1 ⁇ or formula I-l-1 ⁇ :
• each of IRAK, Ring A a , L, L 1 , R 1a , R 2a , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein: X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, ; R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• Ring A is a mono- or bicyclic ring selected from , ,
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO2,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
• each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, or ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• Ring A is a mono- or bicyclic ring selected from , ,
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO2,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR,
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, 2, 3, or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
• each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formala I-m ⁇ above is provided as a compound of formula I-m ⁇ or formula I-m ⁇ :
• each of IRAK, Ring A, Ring B, L, L 1 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , n, p, and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1b is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2b is independently hydrogen, –R 6b , halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O)2R;
• Ring B b is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3b and R 4b is independently hydrogen,–R 6b , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R; R 5b is hydrogen,
• each R 6b is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
• each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formala I-m ⁇ above is provided as a compound of formula I-m ⁇ or formula I-m ⁇ :
• each of IRAK, Ring A b , Ring B b , L, L 1 , R 1b , R 2b , R 3b , X 1 , X 2 , X 3 , n, p, and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH2–,–C(O)–,–C(S)–, or ;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• Ring A is a mono- or bicyclic ring selected from , ,
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1;
• each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH 2 – or–Si(R 2 )–;
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or –N(R)S(O) 2 R;
• Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3 and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, or –N(R)S(O) 2 R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L 1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by–Cy-, -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -
• each–Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen,
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1;
• each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formala I-n ⁇ above is provided as a compound of formula I-n ⁇ or formula I-n ⁇ :
• each of IRAK, Ring A, Ring B, L, L 1 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , n, p, and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety
• L and IRAK are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, ;
• X 2 is a carbon atom or silicon atom;
• X 3 is a bivalent moiety selected from–CH2– or–Si(R2)–;
• R 1c is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• Ring A c is a mono- or bicyclic ring selected from , ,
• each R 2c is independently hydrogen, –R 6c , halogen, –CN, –NO 2 , –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• Ring B c is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 3c and R 4c is independently hydrogen,–R 6c , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5c is hydrogen, C 1-4 aliphatic, or–CN;

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