IRAK decomposition agents and their uses

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.The compounds provided by the present invention are also useful for the study of IRAK enzyme in biological and pathological phenomena; the study of intracellular signaling pathways occurring in body tissues; and the comparative evaluation of novel IRAK inhibitors or IRAK degraders, or other regulators of kinase, signaling pathways, and cytokine levels in vitro or in vivo.

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 132,332 (filed December 30, 2020), the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of one or more interleukin-1 receptor-associated kinases ("IRAKs") by ubiquitination and / or degradation by compounds according to the invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using said compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to numerous cellular processes, and when deficient or imbalanced, it leads to the pathogenesis of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that facilitate the ubiquitination of various proteins in vivo, which are divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. In general, Li et al. (PLOS One, 2008, 3, 1487) entitled "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. Biol., 2014, 21, 301-307) entitled "New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) Title “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled “Roles of F-box proteins in cancer.”

[0005] The UPP plays a key role in the degradation of short-lived regulatory proteins important in a variety of fundamental cellular processes, including cell cycle regulation, cell surface receptor and ion channel regulation, and antigen presentation. The pathway is involved in the pathogenesis of several forms of malignancy, several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting. Many diseases are associated with abnormal UPP and adversely affect the regulation of cell cycle and division, cellular responses to stress and extracellular modulators, neuronal network morphogenesis, cell surface receptors, ion channels, secondary pathways, DNA repair, and organelle biogenesis.

[0006] Abnormalities in this process have recently been implicated in the pathogenesis of several diseases, both congenital and acquired. These diseases fall into two major groups: (a) diseases resulting from loss of function leading to the stabilization of specific proteins, and (b) diseases resulting from gain of function (i.e., aberrant or accelerated degradation of protein targets).

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents and provide a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). In the art, there is a continuing need for effective treatment of diseases, particularly hyperplasia and cancer, such as multiple myeloma.However, non-specific effects and the inability to target and regulate specific classes of proteins (e.g., transcription factors) together remain obstacles to the development of effective anti-cancer drugs.Therefore, small molecule therapeutic agents that affect E3 ligase-mediated protein degradation and target cancer-related proteins, such as interleukin-1 receptor-associated kinase ("IRAK"), hold promise as therapeutic agents.Therefore, there remains a need to find compounds that are IRAK decomposers useful as therapeutic agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Li et al. (PLOS One, 2008, 3, 1487) Title: "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling." [Non-patent document 2] Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) Title: "New insights into ubiquitin E3 ligase mechanism" [Non-patent document 3] Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title: "RING domain E3 ubiquitin ligases." [Non-patent document 4] Spratt et al. (Biochem. 2014, 458, 421-437) Title: "RBR E3 ubiquitin ligases: new structures, new insights, new questions." [Non-patent document 5] Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) Title: "Roles of F-box proteins in cancer." [Non-patent document 6] Crews C,Chemistry & Biology,2010,17(6):551-555;Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention The present application relates to novel bifunctional compounds that function to recruit IRAK kinase to E3 ubiquitin ligase for degradation, as well as methods for their preparation and use. In particular, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of IRAK kinase, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. Monovalent compounds that find utility as inducers of targeted ubiquitination of IRAK kinase, which are then degraded and / or otherwise inhibited by the monovalent compounds described herein, are also provided. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, consistent with the degradation / inhibition of IRAK kinase. Additionally, the present disclosure provides methods of using an effective amount of a compound described herein to treat or alleviate disease conditions, such as cancer, e.g., multiple myeloma.

[0010] The present application further includes bifunctional molecules that link a degradation-inducing moiety to a ligand that binds to an IRAK kinase, the molecules having the following general formula I: [ka] or a pharmaceutically acceptable salt thereof. In general Formula I, each variable is as defined and described herein.

[0011] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective for the targeted modulation of ubiquitination. Such compounds have the formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] The present invention further relates to bifunctional compounds that not only degrade IRAK, but also degrade IMiD substrates, such as Ikaros, Aiolos, or Ikaros and Aiolos.

[0013] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with modulation of signal transduction pathways involving IRAK kinase, including those described herein.

[0014] The compounds provided by the present invention are also useful for studying the IRAK enzyme in biological and pathological phenomena; studying intracellular signaling pathways occurring in body tissues; and comparative evaluation of new IRAK inhibitors or degraders, or other regulators of kinase, signaling pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of one or more IRAK protein kinases. In some embodiments, provided compounds degrade and / or inhibit IRAK-1 / 2 / 3 / 4. In some embodiments, provided compounds degrade IRAK4 and an IMiD substrate, such as Ikaros, Aiolos, or Ikaros and Aiolos.

[0016] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in 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 binds IRAK to DIM; and DIM is a degradation-inducing moiety.

[0017] 2. Compounds and Definitions: The compounds of the present invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0018] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0019] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0020] The term "lower alkyl" refers to C 1~4 " refers to a straight or branched chain alkyl group of the formula: Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0021] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0022] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0023] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0024] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0025] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0026] The term "alkenylene" refers to a divalent 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 substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0027] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] The term "cyclopropyl" refers to a divalent cyclopropyl group.

[0028] The term "halogen" means F, Cl, Br, or I.

[0029] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. As used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0030] The terms "heteroaryl" and "heteroara-," 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 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "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, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, 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. Heteroaryl groups may be monocyclic 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, where the alkyl and heteroaryl portions independently are optionally substituted.

[0031] 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- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0032] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "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 alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. Heterocyclyl groups can contain one or more oxo (C=O) or thioxo (S=O) groups. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0033] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0034] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, 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 substituents may be either the same or different at each position. Combinations of substituents envisioned by the present 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 substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○which can be replaced by); -NO2; -CN; -N3; -(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH,2) 0~4 C(O)SR ○ ; -(CH2) 0~4 C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR-; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0036] R○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0037] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, 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, etc., and 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0043] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0044] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention 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. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0045] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits IRAK kinase with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or have a binding constant.

[0046] As used herein, the term "degrading agent" is defined as a heterobifunctional or monovalent compound that binds and / or inhibits both IRAK kinase and E3 ligase with measurable affinity, resulting in ubiquitination and subsequent degradation of the IRAK kinase. In certain embodiments, a degrading agent has a DC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 As used herein, the term "monovalent" refers to a degrader compound that does not have an E3 ligase binding moiety attached.

[0047] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods 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.

[0048] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0049] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0050] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include 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, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0051] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0052] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in IRAK protein kinase activity between a sample containing a compound of the present invention or a composition thereof and IRAK protein kinase and an equivalent sample containing IRAK protein kinase without the compound or composition thereof present.

[0053] 3. Description of Exemplary Embodiments: As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in 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 binds IRAK to DIM; and DIM is a degradation-inducing moiety.

[0054] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: IRAK is the IRAK4 binding moiety; L is a bivalent moiety that binds IRAK to DIM; and DIM is an E3 ubiquitin ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. IRAK binding part (IRAK)

[0055] In certain embodiments, the present invention provides a compound wherein the IRAK is an IRAK4 binding moiety, whereby the compound has formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM and L are as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O -)R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's x the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spirofused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, optionally taken together with atoms between them, form a 4- to 11-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having, in addition to the atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z, Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] or 1 R y and one R x optionally taken together with the atoms between them, form an 8- to 20-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic or bicyclic ring having 1 to 10 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R z independently, C 1~6 an optionally substituted group selected from a 4- to 9-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, or spirocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring P and Ring Q are optionally fused rings independently selected from phenyl or benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring P and Ring Q are independently optionally substituted with 1 to 2 oxo groups; Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; L x is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently selected from the group consisting of -Cy x and optionally replaced by -, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR-, or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR-, or -CR=CR- is R x or R y together with may form a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -Cy x - is an optionally substituted group selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy x - is optionally substituted with 1 to 2 oxo groups; X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [ka] is a single or double bond; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0056] As described herein: [ka] The core structure shown in FIG. [ka] Includes.

[0057] As generally defined above, each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or two R x The groups, optionally taken together, form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spiro-fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] In some embodiments, R x is hydrogen. In some embodiments, Rx is deuterium. In some embodiments, R x is R z In some embodiments, R x is halogen. In some embodiments, R x In some embodiments, each R x is independently -NO. In some embodiments, R x is -OR. In some embodiments, each R x is independently -SR. In some embodiments, R x is -NR2. In some embodiments, R x is —S(O)R. In some embodiments, R x is —S(O)NR. In some embodiments, R x is -S(O)R. In some embodiments, R x is -CFR2. In some embodiments, R x is -CF2R. In some embodiments, R x is —CF. In some embodiments, R x is -CR2(OR). In some embodiments, R x is -CR2(NR2). In some embodiments, R x is —C(O)R. In some embodiments, R x is —C(O)OR. In some embodiments, R x is —C(O)NR. In some embodiments, eR x Ha-N + (O - )R2. In some embodiments, R x is -OP(O)R. In some embodiments, R x is -OP(O)(OR). In some embodiments, R x is -OP(O)(OR)NR. In some embodiments, R x is -OP(O)(NR). In some embodiments, Rx is -P(O)R. In some embodiments, R x is -SiR. In some embodiments, R x is —Si(OR)R. In some embodiments, R x is -SF5. In some embodiments, R x teeth [ka] In some embodiments, two R x The groups optionally join together to form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R x the groups optionally taken together form an optionally substituted 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spiro-fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0059] In some embodiments, R x teeth [ka] In some embodiments, R x is fluoro. In some embodiments, R x is chloro. In some embodiments, R x is -CFH. In some embodiments, R x is -OMe. In some embodiments, R x is -OEt. In some embodiments, R x In some embodiments, R x is -NMe2. In some embodiments, R x is -SMe. In some embodiments, R x is —S(O)Me. In some embodiments, Rx is —S(O)Me. In some embodiments, R x is -Me. In some embodiments, R x is -Et. In some embodiments, R x In some embodiments, R x is cyclopropyl. In some embodiments, R x is -Ac. In some embodiments, R x is -COMe. In some embodiments, R x is —COH. In some embodiments, R x is -OCF2H. In some embodiments, R x is -OCF3. In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R xteeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] is.

[0060] In some embodiments, each R x is selected from those illustrated in Table 1 below.

[0061] As generally defined above, each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 and R groups on the same atom optionally taken together with atoms between them form a 4- to 11-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having, in addition to the atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] In some embodiments, each R is independently hydrogen. In some embodiments, each R is C 1~6In some embodiments, each R is an optionally substituted group selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 119, 1109, 1111112, 11123, 1124, 1130, 1131, 1140, 1141, 11

[0063] In some embodiments, each R is selected from those depicted in Table 1 below.

[0064] As generally defined above, each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, -SF5, or [ka] or two R ygroups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or one R y and one R x optionally taken together with the atoms between them, form an 8- to 20-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic or bicyclic ring having 1 to 10 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, R y is hydrogen. In some embodiments, R y is deuterium. In some embodiments, R y is R z In some embodiments, R y is halogen. In some embodiments, R y is -CN. In some embodiments, R y is —NO. In some embodiments, R y In some embodiments, R y In some embodiments, R y is -NR2. In some embodiments, R y is —S(O)R. In some embodiments, R y is —S(O)NR. In some embodiments, R y is -S(O)R. In some embodiments, R y is -CFR2. In some embodiments, R y is -CF2R. In some embodiments, R y is —CF. In some embodiments, R y is -CR2(OR). In some embodiments, R y is -CR2(NR2). In some embodiments, R y is —C(O)R. In some embodiments, Ry is —C(O)OR. In some embodiments, R y is —C(O)NR. In some embodiments, R y Ha-N + (O - )R2. In some embodiments, R y is -OP(O)R. In some embodiments, R y is -OP(O)(OR). In some embodiments, R y is -OP(O)(OR)NR. In some embodiments, R y is -OP(O)(NR). In some embodiments, R y is -P(O)R. In some embodiments, R y is -SiR. In some embodiments, R y is —Si(OR)R. In some embodiments, R y is -SF5. In some embodiments, R y teeth [ka] In some embodiments, two R y The groups optionally join together to form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, one R y and one R x optionally taken together with the atoms between them, form an 8- to 20-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic or bicyclic ring having 1 to 10 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, R y is fluoro. In some embodiments, R y is chloro. In some embodiments, R yis -CN. In some embodiments, R y is -CF2Me. In some embodiments, R y is -CFMe2. In some embodiments, R y is -Me. In some embodiments, R y is -OMe. In some embodiments, R y is -OCF3. In some embodiments, R y is fluoro. In some embodiments, R y is cyclopropyl. In some embodiments, R y teeth [ka] In some embodiments, R y teeth [ka] is.

[0067] In some embodiments, R y and R x The combination of and [ka] In some embodiments, R y and R x The combination of and [ka] In some embodiments, R y and R x The combination of and [ka] In some embodiments, R y and R x The combination of and [ka] In some embodiments, R y and R x The combination of and [ka] is.

[0068] In some embodiments, each R y is selected from those illustrated in Table 1 below.

[0069] As generally defined above, each R z independently, C 1~6 An optionally substituted group selected from a 4- to 9-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, or spirocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, R z is C 1~6 In some embodiments, R is an optionally substituted group selected from aliphatic. z is optionally substituted phenyl. In some embodiments, R z is an optionally substituted 4- to 9-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, or spirocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R z is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0071] In some embodiments, each R z is selected from those illustrated in Table 1 below.

[0072] As generally defined above, ring P and ring Q are optionally fused rings independently selected from phenyl or benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring P and ring Q are independently optionally substituted with 1 to 2 oxo groups.

[0073] In some embodiments, ring P is phenyl or benzo. In some embodiments, ring P is a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring P is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring P is optionally substituted with 1 to 2 oxo groups. In some embodiments, ring Q is phenyl or benzo. In some embodiments, ring Q is a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Q is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Q is optionally substituted with 1 to 2 oxo groups.

[0074] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] is.

[0075] In some embodiments, ring P and ring Q are selected from those depicted in Table 1 below.

[0076] As generally defined above, Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1 to 2 oxo groups.

[0077] In some embodiments, Ring T is derived from phenyl. In some embodiments, Ring T is a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is further optionally substituted with 1 to 2 oxo groups.

[0078] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, Ring T is phenyl. In some embodiments, Ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] is.

[0079] In some embodiments, ring T is selected from those depicted in Table 1 below.

[0080] As generally defined above, L x is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently selected from the group consisting of -Cy x and optionally replaced by -, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR-, or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR-, or -CR=CR- is R x or R y may be taken together to form a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0081] In some embodiments, L x is a covalent bond. In some embodiments, L x is C 1~3 wherein one to two methylene units of the chain are independently selected from the group consisting of -Cy x In some embodiments, R in -CR-, -CRF-, -NR-, -N=CR-, or -CR=CR- is optionally replaced by R x or R y may be taken together to form a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments, ring L x is —C(O)N(H)—. In some embodiments, ring Lx is —CHC(O)N(H)—. In some embodiments, ring L x teeth, [ka] In some embodiments, L x is R y Together with [ka] In some embodiments, L x together with Ry, [ka] Form.

[0083] In some embodiments, ring L x is selected from those illustrated in Table 1 below.

[0084] As generally defined above, -Cy x - is an optionally substituted group selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy x - is optionally substituted with 1 to 2 oxo groups.

[0085] In some embodiments, -Cy x - is an optionally substituted group selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. x - is a 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.x - is optionally substituted with 1 to 2 oxo groups.

[0086] In some embodiments, the ring -Cy x - is selected from those illustrated in Table 1 below.

[0087] As described above, X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In some embodiments, X is a covalent bond. In some embodiments, X is a 4- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0089] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] is.

[0090] In some embodiments, X is selected from those depicted in Table 1 below.

[0091] As generally defined above, [ka] is a single or double bond.

[0092] In some embodiments, [ka] In some embodiments, [ka] is a double bond.

[0093] In some embodiments, the ring [ka] is selected from those illustrated in Table 1 below.

[0094] As generally defined above, x and y are each independently 0, 1, 2, 3, or 4.

[0095] In some embodiments, x and y are each independently 0. In some embodiments, x and y are each independently 1. In some embodiments, x and y are each independently 2. In some embodiments, x and y are each independently 3. In some embodiments, x and y are each independently 4.

[0096] In some embodiments, each of x and y is selected from those depicted in Table 1 below.

[0097] In some embodiments, the present invention provides compounds of formula Id-1, where ring P and ring Q form an imidazole ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0098] In some embodiments, the present invention provides compounds of formula Id-2, where ring P and ring Q form a 6-azaindazole ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0099] In some embodiments, the present invention provides compounds of formula Id-3, where ring P and ring Q form an indazole ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0100] In some embodiments, the present invention provides compounds of formula Id-4, where ring P and ring Q form a pyrazolopyridine ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0101] In some embodiments, the present invention provides compounds of formula Id-5, wherein ring P and ring Q form an imidazo[1,2-a]pyridine ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0102] In some embodiments, the present invention provides a compound in which ring Q is benzo and one R x is -OR and X is cyclohexyl, and has formula Id-6: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , R x , R y , ring P, ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0103] In some embodiments, the present invention provides a compound in which rings P and Q form an indazole ring, as shown, and one R x is -OR and X is cyclohexyl, and has formula Id-7: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, L x , R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0104] In some embodiments, IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] is.

[0105] In some embodiments, the IRAK is selected from those depicted in Table 1 below.

[0106] In some embodiments, the present invention relates to a method for treating IRAK comprising the steps of: [ka] whereby the compound of formula Ib, Ib-1, Ib-2, or Ib-3: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in embodiments herein; and HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[1,2-b]pyridazine, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, wherein the heteroaryl is selected from R a and R b is replaced by; R a are H, F, Cl, Br, -CN, -OH, C1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NH(C 1~4 hydroxyalkyl), -NH(C 1~4 fluoroalkyl), -NH(C 1~6 hydroxy-fluoroalkyl), -C(O)NH2, -CH2NHC(O)(C 1~6 alkyl), -CHNHC(O)(C 1~6 hydroxyalkyl), -CH2NHC(O)NH(C 1~6 alkyl), -CH2NHC(O)NHCH2(phenyl), -CH2NHC(O)N(C 1~4 alkyl)2, -CH2NHC(O)O(C 1~4 alkyl), -CHNHC(O)(C 3~6 cycloalkyl), -CH2NHC(O)(tetrahydrofuranyl), -CH2NHC(O)CH2(C 3~6 cycloalkyl), -CH2NHC(O)CH2(tetrahydropyranyl), -CH2NHC(O)CH2(phenyl), -NHC(O)(C 1~4 alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl; R b is H or -NH2; R1 is (I C 1~6 Alkyl, C 1~6 Alkyl C 3~6 Cycloalkyl, C 1~6 Fluoroalkyl, C 1~6 Hydroxyalkyl, C 1~8 Hydroxy-fluoroalkyl, -(C 1~6 alkylenyl)O(C 1~4 alkyl), -(C 1~6 alkylenyl)O(C 1~4 fluoroalkyl), -(C 1~6 Fluoroalkenyl)O(C 1~4 alkyl), -(C 1~6Fluoroalkenyl)O(C 1~4 Deuteroalkyl), -(C 1~6 Fluoroalkenyl)O(C 1~4 fluoroalkyl), -(C 1~4 Fluoroalkenyl)C(C 3~6 cycloalkyl)2(OH), -(C 1~4 alkylenyl)NHC(O)(C 1~4 alkylenyl)OC(O)(C 1~3 alkyl), -(C 1~6 alkylenyl)NHS(O)2(C 1~4 alkyl), -(C 1~6 alkylenyl)P(O)(C 1~4 alkoxy)2, -(C 1~6 Fluoroalkenyl)NH(C 1~4 alkyl), -(C 1~6 alkylenyl)C(O)NH(C 1~4 alkyl), -(C 1~6 Fluoroalkenyl)C(O)NH(C 1~4 alkyl), -(C 1~6 Fluoroalkenyl)C(O)NH(C 1~4 hydroxyalkyl), or -(C 1~6 Fluoroalkenyl)OP(O)(OH)2; (ii) -(C 1~3 Alkylenyl)R x , -(C 1~3 Fluoroalkenyl)R x , -(C 1~3 alkylenyl)C(O)R x , -(C 1~3 (alkylenyl)C(O)NHR x , -(C 1~3 Fluoroalkenyl)C(O)R x or -CHCF=(tetrahydropyranyl), where R x is C 3~6a cyclic group selected from cycloalkyl, tetrazolyl, 1,1-dioxidetetrahydrothiophenyl, 1,1-dioxidethiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl, and triazinyl, wherein each cyclic group is substituted with 0 to 3 substituents independently selected from F, —OH, —CH, —C(CH)OH, —OCH, —C(O)CHCN, —S(O)CH, —S(O)NH, —NHC(O)CH, —N(S(O)CH)—, —CHCH(acetamidophenyl), —CHCH(methoxyphenyl), —CHCH(sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl; (iii) C 3~6 Cycloalkyl or C 4~6 cycloalkenyl, each of which is selected from the group consisting of F, —OH, —CN, C 1~3 Alkyl, C 1~3 Alkoxy, -S(C 1~3 alkyl), -NO2, -S(O)2(C 1~3 alkyl), C 1~4 Hydroxyalkyl, -C(C 1~3 alkyl)(OH)(C 3~6 cycloalkyl), -CHC(O)NH(C 1~3 alkyl), -NHC(O)(C 1~3 alkyl), -NHC(O)(C 1~4 hydroxyalkyl), -C(O)NH(C 1~3 alkyl), -C(O)NH(C 1~3 Deuteroalkyl), -C(O)NH(C 3~6 cycloalkyl), -NHC(O)O(C 1~3 alkyl), -NHS(O)2(C 1~3 substituted with 0 to 3 substituents independently selected from alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl; (iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each of which is selected from the group consisting of —OH, C 1~3 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, C 1~3 Alkoxy, -C(O)(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH(C 1~4 alkyl), -NH(C 1~3 alkyl), -N(C 1~3 alkyl)2, -O(C 1~3 Alkylenyl)N(C 1~3 substituted with 0 to 1 substituents selected from -C(O)(methylsulfonylazetidinyl), ... (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol, tetrahydrobenzo[d]thiazol-2-amine, or 1,3-diazaspiro[4.5]decane-2,4-dione and R2 is (I C 1~7 Alkyl or C 2~6 alkenyl, each substituted with 0 to 3 substituents independently selected from F, —OH, and —CN; —(C 1~4 alkylenyl)O(C 1~4 alkyl), -(C 1~4 alkylenyl)O(C 1~4 fluoroalkyl), -(C 1~6 alkylenyl)NH2, -(C 1~6 alkylenyl)S(O)2(C 1~3 alkyl), -(C 1~6 Fluoroalkenyl)NH(C 1~3 alkyl), or -(C 1~6 alkylenyl)NHC(O)(C1~4 fluoroalkyl); (ii) -(C 1~4 Alkylenyl)R y where R y is C 3~6 cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each of which is selected from the group consisting of F, —OH, and C 1~3 substituted with 0 to 2 substituents independently selected from alkyl; (iii) C 3~6 cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each of which is selected from the group consisting of F, —OH, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, -C(O)(C 1~3 alkyl), -C(O)(C 1~3 fluoroalkyl), -C(O)(C 1~3 cyanoalkyl), -C(O)O(C 1~3 alkyl), -C(O)NH2, -C(O)NH(C 1~3 alkyl), -C(O)(difluorophenyl), -NH2, -NH(C 1~3 alkyl), -NH(C 1~3 fluoroalkyl), -NH(oxetanyl), -NHC(O)(C 1~3 alkyl), -NHC(O)(C 1~3 fluoroalkyl), -NHC(O)(C 3~6 cycloalkyl), -NHC(O)(fluorophenyl), -S(O)2(C 1~3 substituted with 0 to 3 substituents independently selected from alkyl), imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and methoxypyrimidinyl; (iv) adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl, bicyclo[1.1.1]pentanyl, or hydroxy-bicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or indazolyl, each of which is selected from the group consisting of F, Cl, —OH, —CN, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Fluoroalkyl, C 1~4 Cyanoalkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl, -(C 1~3 alkylenyl)O(C 1~3 alkyl), -(C 1~3 alkylenyl)O(C 1~3 fluoroalkyl), -C(O)NH2, -C(O)NH(C 1~3 alkyl), -NHC(O)(C 1~3 alkyl), -NHC(O)S(O)2(C 1~3 alkyl), -S(O)2NH2, -S(O)2(C 1~3 substituted with 0 to 2 substituents independently selected from alkyl), pyrazolyl, methylpyrazolyl, imidazolyl, triazolyl, methyltetrazolyl, ethyltetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and tetrahydropyranyl; and; As defined and described in WO 2015 / 103453 and US 2015 / 0191464, each of which is incorporated by reference in its entirety.

[0107] In certain embodiments, the present invention relates to an IRAK inhibitor. [ka] whereby formula Ic, Ic-1, Ic-2, or Ic-3: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in embodiments herein, and HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and imidazolo[4,5-d]pyrimidinyl, wherein the heteroaryl is attached to the pyridinyl group of the compound of Formula (I) through a nitrogen ring atom in the heteroaryl, and the heteroaryl is selected from 0 to 2 R b is replaced by; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl, or dihydroisoxazolyl, each of which is R a is replaced by; R3 is C 2~3 Alkyl, C 2~3 Fluoroalkyl, C 3~4 Hydroxyalkyl, or C 3~6 a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein the cyclic group is selected from F, —OH, C 1~2 substituted with 0 to 2 substituents independently selected from alkyl, and -CH2CHF2; R a teeth: (i) H, F, C1, -OH, -CN, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~4 Cyanoalkyl, C 1~6 Hydroxyalkyl, C 1~5 Hydroxy-fluoroalkyl, C 2~4 Alkenyl, C 1~6 Aminoalkyl, -(CH2) 1~3 NHR y , -(CH2) 1~3 NR y R y, -CH2CH(OH)(phenyl), -CH(CH2OH)(phenyl), -CH2CH(OH)CH2(phenyl), -CH2CH(OH)CH2O(methoxyphenyl), -CH2CH(NH2)CH2(phenyl), -(CH2CH2O)4H, -(CH2) 1~3 O(C 1~3 alkyl), -CH2CH(OH)CH2O(C 1~3 alkyl), -CHC(O)(C 1~3 alkyl), -CH2C(O)NR y R y , -(CH2) 1~3 NR y C(O)(C 1~3 alkyl), -CHC(O)O(C 1~3 alkyl), -C(O)NH2, -CH2NR y C(O)NH2, -(CH2) 1~2 NR y C(O)O(C 1~2 alkyl), -(CR y R y ) 1~5 OC(O)CH2NR y R y , -CH2CH2S(O)2CH3, -CH2S(O)2(C 1~3 -alkyl), -CH2S(O)2 (phenyl), or -NH (aminocyclohexyl); or (ii) -(CH2) 0~3 R z or -(CH2) 0~1 C(O)R z where R z is C 3~6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, dioxopyrimidinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxolanyl, or 8-azabicyclo[3.2.1]octanyl, each of which is selected from the group consisting of F, —CN, —OH, —NR y R y , C 1~3 Alkyl, C1~3 Fluoroalkyl, C 1~3 Hydroxyalkyl, -CH(phenyl)2, -O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)(C 1~4 Deuteroalkyl), -C(O)(C 1~5 hydroxyalkyl), -C(O)(C 1~3 fluoroalkyl), -C(O)(C 3~6 cycloalkyl), -C(O)O(C 1~3 alkyl), -C(O)NR y R y , -C(O)(phenyl), -C(O)(pyridinyl), -C(O)CH2(C 3~6 cycloalkyl), -C(O)O(C 1~4 alkyl), -NH(C 1~4 alkyl), -NH(C 1~3 fluoroalkyl), -NHC(O)CH3, -NHC(O)O(C 1~3 alkyl), -NHC(O)OC(CH3)3, -S(O)2(C 1~3 alkyl), -OS(O)2(C 1~3 substituted with 0 to 4 independent substituents selected from alkyl), methyloxadiazolyl, and pyrimidinyl; and Each R b is independently selected from H, Cl, —CN, —NH, and —C(O)NH, where the heteroaryl is attached to the pyridinyl group through a nitrogen atom in the heteroaryl; and Each R y are independently H or C 1~2 is alkyl; As defined and described in WO 2016 / 210034 and US 2018 / 0186799, each of which is incorporated by reference in its entirety.

[0108] In some embodiments, IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] is. Ligase binding moiety (LBM)

[0109] As defined herein and described below, formulas may be expressed using square brackets, e.g., [ka] When depicted as: L is attached to a modifiable carbon, oxygen, or nitrogen atom in DIM or LBM, including substitution or replacement of the defined group in DIM or LBM.

[0110] In some embodiments, the DIM is an LBM. In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R 2are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are 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)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 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] -(R 2 ) m is depicted on ring B, this -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A, and also may be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 This R 4 group or R 5 It replaces the -R group. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 This R 3 It replaces the base.

[0112] In some embodiments, the compound of formula I-aa has formula I-aa' or formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0113] In certain embodiments, the present invention provides a method for treating a cytoplasmic ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Each R 2 are 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are 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)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 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0114] -(R 2 ) m is depicted on ring B, this -(R 2 ) mIt is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A, and also may be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 This R 4 group or R 5 It replaces the -R group. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 This R 3 It replaces the base.

[0115] In some embodiments, the compound of formula I-cc has formula I-cc' or formula I-cc'': [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring A, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0116] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 and R 3a each independently represents hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are 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)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 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments, the compound of formula I-dd has formula I-dd' or formula I-dd'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m, and p are each as defined above.

[0118] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein (FBG) ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 and R 3aeach independently represents 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are 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)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 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0119] In some embodiments, the compound of formula I-ee has formula I-ee' or formula I-ee'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1 , n, m, and p are each as defined above.

[0120] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, whereby the LBM has the formula I-ff: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from: Each or R 2 and R 3a are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are 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)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 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, the compound of formula I-ff has formula I-ff' or formula I-ff'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n, and p are as defined above.

[0122] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, thereby providing a ubiquitin ligase having the formula I-gg: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 , R3a , and R 4 each independently represents 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them as needed, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0123] In some embodiments, the compound of formula I-gg has formula I-gg' or formula I-gg'': [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1 , m, n, and p are as defined above.

[0124] In certain embodiments, the present invention provides a method for treating a leukemia virus (LEV) comprising administering to a patient a therapeutically effective amount of at least one LBM ... at least one LBM of formula I-hh: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; R 1 is absent, hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0125] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0126] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0127] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom where Ring E or Ring G is fused to Ring F.

[0128] In some embodiments, the compound of formula I-hh has formula I-hh' or formula I-hh'': [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring E, Ring F, Ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0129] In certain embodiments, the present invention provides a method for treating a leukemia virus (LEV) comprising administering to a patient a therapeutically effective amount of an LBM ..., wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a polypeptide of formula I-hh-1 or I-hh-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and R 4 , R 10 , R 11 , R 15 , W 1 , W 2 and X are as defined in WO 2019 / 099868, each of which is incorporated by reference in its entirety.

[0130] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0131] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0132] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom where Ring E or Ring G is fused to Ring F.

[0133] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein (FBG) ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl containing 0-3 nitrogens, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring E, ring F, and ring G are independently optionally substituted with 1-2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0134] [ka] If the attachment point of is drawn on ring E, ring F, or ring G, then this [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0135] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0136] In some embodiments, the compound of formula I-ii above is represented by formula I-ii' or formula I-ii: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, L, Ring E, Ring F, Ring G, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0137] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; R 1 is absent, hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring H is a 7- to 9-membered, saturated or partially unsaturated fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, or 4.

[0138] [ka] If the attachment point of is drawn on ring E or ring H, then [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0139] -(R 2 ) m When the attachment points of -(R 2 ) mIt is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0140] [ka] When the attachment points of are depicted on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0141] In some embodiments, the compound of formula I-jj has formula I-jj' or formula I-jj'': [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring E, Ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0142] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, thereby representing the formula I-kk: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring H is a 7- to 9-membered, saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0143] [ka] If the attachment point of is drawn on ring E or ring H, then [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0144] -(R 2 ) m When the attachment points of -(R 2 ) mIt is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0145] [ka] When the attachment points of are depicted on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0146] In some embodiments, the compound of formula I-kk has formula I-kk' or formula I-kk'': [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring E, Ring H, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0147] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; R 1 is absent, hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring K is a 7- to 12-membered, saturated or partially unsaturated fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, or 4.

[0148] [ka] is illustrated on ring I, ring J, and ring K, then [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0149] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0150] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0151] In some embodiments, the compound of formula I-ll has formula I-ll' or formula I-ll: [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0152] In certain embodiments, the present invention provides compounds of formula I-mm: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring K is a 7- to 12-membered, saturated or partially unsaturated, fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0153] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0154] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0155] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0156] In some embodiments, the compound of formula I-mm has formula I-mm' or formula I-mm'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0157] As noted above, in another aspect, the present invention provides compounds of formula I-nn: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring M is, [ka] Selected from; X 1 , X 6 , and X 7 each independently represents a covalent bond, —CH—, —CHCF—, —SO—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 3 and X 5 each is independently a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] [ka] is a trivalent moiety selected from: Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3a are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C1~4 Is aliphatic; or R 7 and X 1 or X 3 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on the same carbon 7 groups, optionally taken together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on adjacent carbons 7 groups, optionally taken together with the atoms therebetween, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Ring D is selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0158] X, as defined above and described herein; 1 , X 6 , and X 7 each independently represents a covalent bond, —CH—, —C(R)—, —C(O)—, —C(S)—, —CH(R)—, —CH(CF)—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR)—, —S(O)—, —S(O)—, or [ka] is a divalent moiety selected from

[0159] In some embodiments, X 1 , X 6 , and X 7 Each of X is independently a covalent bond. 1 , X 6 , and X 7 Each of X is independently -CH-. 1 , X 6 , and X 7 Each of X is independently -CR-. 1 , X 6 , and X 7 Each of X is independently -C(O)-. 1 , X 6 , and X 7 Each of X is independently -C(S)-. 1 , X 6 , and X 7 Each of X is independently -CH(R)-. 1 , X 6 , and X 7 Each of X is independently -CH(CF3)-. 1 , X 6, and X 7 Each of X is independently -P(O)(OR)-. 1 , X 6 , and X 7 Each of X is independently -P(O)(R)-. 1 , X 6 , and X 7 Each of X is independently -P(O)NR-. 1 , X 6 , and X 7 Each of X is independently -S(O)-. 1 , X 6 , and X 7 Each of X is independently -S(O)-. 1 , X 6 , and X 7 Each of the [ka] is.

[0160] In some embodiments, X 1 , X 6 , and X 7 are each independently selected from those depicted in Table 1 below.

[0161] X, as defined above and described herein; 2 is a carbon atom, a nitrogen atom, or a silicon atom.

[0162] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a nitrogen atom. In some embodiments, X 2 is a silicon atom.

[0163] In some embodiments, X 2 is selected from those illustrated in Table 1 below.

[0164] X, as defined above and described herein; 3 is a divalent moiety selected from -CH2-, -CR2-, -NR-, -CF2-, -CHF-, -S-, -CH(R)-, -SiR2-, or -O-.

[0165] In some embodiments, X 3 and X 5 Each of X is independently -CH. 3 and X 5 Each of X is independently -CR-. 3 and X 5 Each of X is independently -NR. 3 and X 5 Each of X is independently -CF. 3 and X 5 Each of X is independently -CHF. 3 and X 5 Each of X is independently -S. 3 and X 5 Each of X is independently -CH(R). 3 and X 5 Each of X is independently -SiR2. 3 and X 5 Each of is independently -O-.

[0166] In some embodiments, X 3 and X 5 are each independently selected from those depicted in Table 1 below.

[0167] X, as defined above and described herein; 4 teeth, [ka] is a trivalent moiety selected from

[0168] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] is.

[0169] In some embodiments, X 4 is selected from those illustrated in Table 1 below.

[0170] R as defined above and described herein 1represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, optionally substituted C 1~4 Aliphatic or R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0171] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -P(O)(OR). In some embodiments, R 1 is -P(O)(NR2)OR. In some embodiments, R 1 is —P(O)(NR) . In some embodiments, R 1 is —Si(OH)R. In some embodiments, R 1 is —Si(OH)R. In some embodiments, R 1 is -SiR. In some embodiments, R 1 is replaced by C 1~4 In some embodiments, R1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0172] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0173] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group, and the optionally substituted group is C 1~6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; or two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0174] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted C 1~6It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0175] In some embodiments, R is selected from those depicted in Table 1 below.

[0176] R as defined above and described herein 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -Si(OH)2R, -Si(OH)R2, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O) R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -OC(O)R, -OC(O)NR2, -O P(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N (R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0177] In some embodiments, R 2 and / or R 3ais hydrogen. In some embodiments, R 2 and / or R 3a is deuterium. In some embodiments, R 2 and / or R 3a -R 6 In some embodiments, R 2 and / or R 3a is halogen. In some embodiments, R 2 and / or R 3a In some embodiments, R 2 and / or R 3a is —NO. In some embodiments, R 2 and / or R 3a is -OR. In some embodiments, R 2 and / or R 3a is —Si(OH)R. In some embodiments, R 2 and / or R 3a is —Si(OH)R. In some embodiments, R 2 and / or R 3a is -SR. In some embodiments, R 2 and / or R 3a is -NR2. In some embodiments, R 2 and / or R 3a is -SiR. In some embodiments, R 2 and / or R 3a is —S(O)R. In some embodiments, R 2 and / or R 3a is —S(O)NR. In some embodiments, R 2 and / or R 3a is -S(O)R. In some embodiments, R 2 and / or R 3a is —C(O)R. In some embodiments, R 2 and / or R 3ais —C(O)OR. In some embodiments, R 2 and / or R 3a is —C(O)NR. In some embodiments, R 2 and / or R 3a is —C(O)N(R)OR. In some embodiments, R 2 and / or R 3a is —C(R)N(R)C(O)R. In some embodiments, R 2 and / or R 3a is —C(R)N(R)C(O)NR. In some embodiments, R 2 and / or R 3a is —OC(O)R. In some embodiments, R 2 and / or R 3a is —OC(O)NR. In some embodiments, R 2 and / or R 3a is -OP(O)R. In some embodiments, R 2 and / or R 3a is -OP(O)(OR). In some embodiments, R 2 and / or R 3a is -OP(O)(OR)NR. In some embodiments, R 2 and / or R 3a is -OP(O)(NR)-. In some embodiments, R 2 and / or R 3a is —N(R)C(O)OR. In some embodiments, R 2 and / or R 3a is —N(R)C(O)R. In some embodiments, R 2 and / or R 3a is —N(R)C(O)NR. In some embodiments, R 2 and / or R 3a is -NP(O)R. In some embodiments, R 2 and / or R 3ais —N(R)P(O)(OR). In some embodiments, R 2 and / or R 3a is —N(R)P(O)(OR)NR. In some embodiments, R 2 and / or R 3a is —N(R)P(O)(NR). In some embodiments, R 2 and / or R 3a is -N(R)S(O)R.

[0178] In some embodiments, R 2 and / or R 3a is —OH. In some embodiments, R 2 and / or R 3a is -NH2. In some embodiments, R 2 and / or R 3a is —CH 2 NH 2 . In some embodiments, R 2 and / or R 3a is —CHNHCOMe. In some embodiments, R 2 and / or R 3a is —CHNHCONHMe. In some embodiments, R 2 and / or R 3a is -NHCOMe. In some embodiments, R 2 and / or R 3a is -NHCONHEt. In some embodiments, R 2 and / or R 3a is -SiMe. In some embodiments, R 2 and / or R 3a is —SiMeOH. In some embodiments, R 2 and / or R 3a is —SiMe(OH). In some embodiments, R 2 and / or R 3a teeth, [ka] In some embodiments, R 2 and / or R 3a is Br. In some embodiments, R 2 and / or R 3a is Cl. In some embodiments, R 2 and / or R 3a is F. In some embodiments, R 2 and / or R 3a is Me. In some embodiments, R 2 and / or R 3a is -NHMe. In some embodiments, R 2 and / or R 3a is -NMe2. In some embodiments, R 2 and / or R 3a is -NHCO2Et. In some embodiments, R 2 and / or R 3a In some embodiments, R 2 and / or R 3a is -CHPh. In some embodiments, R 2 and / or R 3a is -NHCO2tBu. In some embodiments, R 2 and / or R 3a is -CO2tBu. In some embodiments, R 2 and / or R 3a is -OMe. In some embodiments, R 2 and / or R 3a is -CF3.

[0179] In some embodiments, R 2 and R 3a is selected from those illustrated in Table 1 below.

[0180] R as defined above and described herein 3represents hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R )C(O)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O)2NR2, -N(R)P(O)(OR)2, -N(R)P(O )(OR)NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, or -Si(R)3.

[0181] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 In some embodiments, R 3 is -NR2. In some embodiments, R 3 In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is —C(O)R. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3 is —C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, R3 is —OC(O)NR. In some embodiments, R 3 is -OP(O)(OR). In some embodiments, R 3 is -OP(O)(NR). In some embodiments, R 3 is -OP(O)(OR)NR. In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)OR. In some embodiments, R 3 is —N(R)C(O)NR. In some embodiments, R 3 is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R 3 is —N(R)P(O)(OR)NR. In some embodiments, R 3 is -P(O)(OR). In some embodiments, R 3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3 is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R 3 is -Si(R)3.

[0182] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0183] In some embodiments, R 3 is selected from those illustrated in Table 1.

[0184] As defined above and described herein, each R 4 are independently hydrogen, deuterium, -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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

[0185] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 Ha-R 6 In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is —NO. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is -NR2. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)NR. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is —C(O)R. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —C(O)NR. In some embodiments, R 4 is —C(O)N(R)OR. In some embodiments, R 4 is -OC(O)R. In some embodiments, R 4is —OC(O)NR. In some embodiments, R 4 is —N(R)C(O)OR. In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)NR. In some embodiments, R 4 is —N(R)S(O)R. In some embodiments, R 4 is -P(O)(OR). In some embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0186] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0187] In some embodiments, R 4 is selected from those illustrated in Table 1.

[0188] R as defined above and described herein 5 is hydrogen, deuterium, optionally substituted C 1~4 It is aliphatic, or -CN.

[0189] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is replaced by C 1~4 In some embodiments, R 5 is -CN.

[0190] In some embodiments, R 5 is selected from those illustrated in Table 1.

[0191] As defined above and described herein, each R 6 independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0192] In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0193] In some embodiments, R 6 is selected from those illustrated in Table 1.

[0194] As generally defined above, each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1~4 Aliphatic or R 1 and X 1 or X 3and together with the atoms between them form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or two R on the same carbon 7 The groups may optionally be joined together with the atoms between them to form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or two R on adjacent carbons may form a heterocyclic ring. 7 The groups, optionally taken together with the atoms between them, form a 3- to 7-membered saturated, partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic ring or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0195] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 is -S(O)R. In some embodiments, R 7 is —S(O)R. In some embodiments, R 7 is -NR2. In some embodiments, R 7 is —Si(R). In some embodiments, R 7 is -P(O)(R). In some embodiments, R 7 is -P(O)(OR). In some embodiments, R 7is -P(O)(NR2)OR. In some embodiments, R 7 is —P(O)(NR) . In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is replaced by C 1~4 In some embodiments, R 7 and X 1 or X 3 and together with the atoms between them form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R on the same carbon 7 The groups, optionally taken together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R on adjacent carbons 7 The groups, optionally taken together with the atoms between them, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R on adjacent carbons 7 The groups, optionally taken together with the atoms between them, form a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic ring or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0196] In some embodiments, R 7 is hydrogen, halogen, -CN, -OR, -NR2, or C 1~4 In some embodiments, R 7 is hydrogen, halogen, -CN, or C 1~4In some embodiments, R 7 is fluoro. In some embodiments, two R 7 The groups, optionally taken together with the atoms between them, form a 3- or 4-membered spiro-fused ring.

[0197] In some embodiments, R 7 is selected from those illustrated in Table 1 below.

[0198] As defined above and described herein, ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from:

[0199] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0200] In some embodiments, ring A is selected from those depicted in Table 1 below.

[0201] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0202] In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a fused 5- to 7-membered, saturated or partially unsaturated carbocyclyl. In some embodiments, ring B is a fused 5- to 7-membered, saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0203] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0204] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0205] As defined above and described herein, Ring C is [ka] is a monocyclic or bicyclic ring selected from:

[0206] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0207] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0208] In some embodiments, ring C is [ka] [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0209] In some embodiments, ring C is selected from those depicted in Table 1 below.

[0210] As defined above and described herein, ring D is a ring selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0211] In some embodiments, ring D is a 6- to 10-membered aryl. In some embodiments, ring D is a 6- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is phenyl. In some embodiments, ring D is pyridinyl.

[0212] In some embodiments, ring D is selected from those depicted in Table 1 below.

[0213] As defined above and described herein, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein rings E, F, and G are independently optionally substituted with 1 to 2 oxo groups.

[0214] In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups.

[0215] In some embodiments, ring F is [ka] is.

[0216] In some embodiments, each of ring E and ring G is independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] is.

[0217] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] is.

[0218] In some embodiments, ring E, ring F, and ring G are selected from those depicted in Table 1 below.

[0219] As defined above and described herein, Ring H is a 7- to 9-membered, saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups.

[0220] In some embodiments, Ring H is a 7- to 9-membered, saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups.

[0221] As defined above and described herein, each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0222] In some embodiments, each of ring I and ring J is independently a 6-membered aryl. In some embodiments, each of ring I and ring J is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of ring I and ring J is independently a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0223] In some embodiments, ring I and ring J are selected from those depicted in Table 1 below.

[0224] As defined above and described herein, ring K is a fused ring selected from 7- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein ring H is optionally further substituted with 1 to 2 oxo groups.

[0225] In some embodiments, ring K is a fused ring selected from a 7- to 12-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring K is a 7- to 12-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

[0226] In some embodiments, ring K is selected from those depicted in Table 1 below.

[0227] As defined above and described herein, ring M is [ka] is selected from.

[0228] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] is.

[0229] In some embodiments, ring M is selected from those depicted in Table 1 below.

[0230] As defined above and described herein, L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-;

[0231] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~3 In some embodiments, L 1 is -CH-. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D)2-. In some embodiments, L 1 is -CHCH-. In some embodiments, L 1 In some embodiments, L 1 is -CHNR-. In some embodiments, L 1 or -O-. In some embodiments, L 1 is —CH2O—. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1is —C(O)O—. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is —S(O)—. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -NRS(O)-. In some embodiments, L 1 is -S(O)NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is -C(O)NR-.

[0232] In some embodiments, ring L 1 is selected from those illustrated in Table 1 below.

[0233] As defined above and described herein, [ka] is a single or double bond.

[0234] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0235] In some embodiments, [ka] is selected from those illustrated in Table 1 below.

[0236] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0237] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[0238] In some embodiments, m is selected from those depicted in Table 1 below.

[0239] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0240] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0241] In some embodiments, n is selected from those depicted in Table 1 below.

[0242] As defined above and described herein, p is 0 or 1.

[0243] In some embodiments, p is 0. In some embodiments, p is 1.

[0244] In some embodiments, p is selected from those depicted in Table 1 below.

[0245] As defined above and described herein, q is 0, 1, 2, 3, or 4.

[0246] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0247] In some embodiments, q is selected from those depicted in Table 1 below.

[0248] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0249] In some embodiments, the LBM is selected from those in Table 1 below.

[0250] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula Ie-1: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , rings A and m, and L and L of the IRAK moiety x , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0251] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula Ie-2: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, L, and L of the IRAK moiety x , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0252] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-OC 1~6 alkyl, x is 0, ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-1: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0253] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is -OMe, x is 0, ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-2: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0254] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] wherein x is 0, ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-3: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0255] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-OC 1~6 alkyl and L is [ka] wherein x is 0, ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-4: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0256] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is -OMe and L is [ka] wherein x is 0, ring Q and ring P together form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-5: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0257] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-OC 1~6 alkyl, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-6: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0258] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2is -OMe, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-7: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0259] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-8: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0260] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-OC 1~6 alkyl and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-9: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0261] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is -OMe and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-10: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0262] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R x is methyl, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-11: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0263] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is methyl, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-12: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0264] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is methyl, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-13: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R yEach of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0265] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-C 1~6 alkyl, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-14: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0266] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is methyl, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-15: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0267] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 Ga-C 1~6 alkyl and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-16: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0268] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is methyl and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-17: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0269] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is halo, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-18: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0270] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is fluoro, x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-19: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0271] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is the halo and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-20: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0272] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is fluoro and L is [ka] wherein x is 0, ring Q and ring P together form a 6-azaindazole ring, and X is cyclohexyl, and the compound represented by formula If-21: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0273] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R x is chloro, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-22: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0274] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is chloro, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-23: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0275] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R x is -OMe, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-24: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0276] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is -OMe, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-25: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R yEach of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0277] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R x is -OMe, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-26: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0278] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is -OMe, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-27: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0279] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R x is —S(O)Me, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-28: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0280] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is —S(O)Me, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-29: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0281] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is a halo, x is 1, and R x is -OMe, ring Q and ring P form a 6-azaindazole ring, and X is cyclobutyl, and the compound represented by formula If-30: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0282] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is fluoro, x is 1, and R x is -OMe, ring Q and ring P form a 6-azaindazole ring, and X is cyclobutyl, and the compound represented by formula If-31: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0283] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is the halo and L is [ka] where x is 1 and R x is -OMe, ring Q and ring P form a 6-azaindazole ring, and X is cyclobutyl, and the compound represented by formula If-32: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1, X 2 , X 3 , R 1 , R 2 , L 1 and ring A, IRAK moiety and L x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0284] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where m is 1 and R 2 is fluoro and L is [ka] where x is 1 and R x is -OMe, ring Q and ring P form a 6-azaindazole ring, and X is cyclobutyl, and the compound represented by formula If-33: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and ring A, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0285] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] where x is 1 and R xis -SO2Me, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-34: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , and rings A, L, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0286] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] where x is 1 and R x is -SO2Me, ring Q and ring P form an indazole ring, and X is cyclohexyl, and the compound represented by formula If-35: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, and L of the IRAK moiety x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0287] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and R1 is cyclohexyl, and the compound of formula If-36: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 and each of R2 and HET of rings A, L, and the IRAK moiety, both alone and in combination, are as defined above and as described in embodiments herein.

[0288] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] and R1 is cyclohexyl, and the compound of formula If-37: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 and ring A, and each of R2 and HET of the IRAK moiety, both alone and in combination, are as defined above and as described in embodiments herein.

[0289] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P together form an imidazo[1,2-a]pyridine ring, and X is cyclohexyl, and the compound represented by formula Ie-3: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, L, and L of the IRAK moiety x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0290] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring Q is benzo and one R x is —OR and X is cyclohexyl, and the compound of formula Ie-4: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, L, and L of the IRAK moiety x , ring P, ring T, R, R x , R yEach of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0291] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, and one R x is —OR and X is cyclohexyl, and the compound of formula Ie-5: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A, and m, L, and L of the IRAK moiety x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0292] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring Q is benzo and one R x is —OR and X is cyclohexyl, and the compound of formula Ie-6: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , R 1 , R 2 , ring A, and m, L, and L of the IRAK moietyx , ring P, ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0293] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, and one R x is —OR and X is cyclohexyl, and the compound of formula Ie-7: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , R 1 , R 2 , ring A, and m, L, and L of the IRAK moiety x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0294] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] and ring Q is benzo and one R x is —OR and X is cyclohexyl, the compound of formula Ie-8: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , R 1 , R 2 , ring A, and m, and L of the IRAK moiety x , ring P, ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0295] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] wherein ring Q and ring P form an indazole ring, and one R x is —OR and X is cyclohexyl, the compound of formula Ie-9: [ka] or a pharmaceutically acceptable salt thereof, wherein X of LBM is 1 , R 1 , R 2 , ring A, and m, and L of the IRAK moiety x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0296] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring Q is benzo and one R xis —OR and X is cyclohexyl, the compound of formula Ie-10: [ka] or a pharmaceutically acceptable salt thereof, wherein R of LBM is 2 and m, L, and L of the IRAK part x , ring P, ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0297] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, and one R x is —OR and X is cyclohexyl, the compound of formula Ie-11: [ka] or a pharmaceutically acceptable salt thereof, wherein R of LBM is 2 and m, L, and L of the IRAK portion x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0298] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring P and ring Q together form an indazole ring, and the ring P is represented by formula Ie-12: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 3a , R 7 , n, q, X, L x , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0299] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring P and ring Q together form a 6-azaindazole ring, and the ring P is represented by formula Ie-13: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 3a , R 7 , n, q, X, L x , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0300] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring P and ring Q together form an indazole ring, and the ring P is represented by formula Ie-14: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , n, X, Lx , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0301] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring P and ring Q together form a 6-azaindazole ring, and the ring P is represented by formula Ie-15: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , n, X, L x , ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0302] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and ring Q is benzo and one R x is —OR and X is cyclohexyl, the compound of formula Ie-16: [ka] or a pharmaceutically acceptable salt thereof, wherein R of LBM is 3a and n, L, and L of the IRAK portion x , ring P, ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0303] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, and one R x is —OR and X is cyclohexyl, the compound of formula Ie-17: [ka] or a pharmaceutically acceptable salt thereof, wherein R of LBM is 3a and n, L, and L of the IRAK portion x , ring T, R, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0304] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, n is 1, and R 3a Ga-OC 1~6 alkyl, x is 1, and R x is -OMe and X is cyclohexyl, and the compound of formula Ie-18: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 7 , q, L x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0305] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring Q and ring P form an indazole ring, n is 1, and R 3a is -OMe, x is 1, and R x is -OMe and X is cyclohexyl, and the compound of formula Ie-19: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 7 , q, L x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0306] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] wherein ring Q and ring P form an indazole ring, n is 1, and R 3a Ga-OC 1~6 alkyl, x is 1, and R x is -OMe and X is cyclohexyl, and the compound of formula Ie-20: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 7 , q, L x , ring T, Ry Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0307] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and L is [ka] wherein ring Q and ring P form an indazole ring, n is 1, and R 3a is -OMe, x is 1, and R x is -OMe and X is cyclohexyl, and the compound of formula Ie-21: [ka] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, L 1 , R 7 , q, L x , ring T, R y Each of , and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0308] In some embodiments, the LBM is prepared using the methods described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017, 13, 675; WO 2017 / 176708; US 2017 / 0281784; WO 2017 / 161119; WO 2017 / 176957; WO 2017 / 176958; WO 2015 / 160845; US 2015 / 0291562; WO 2016 / 197032; WO 2016 / 105518; US 2018 / 0009779; WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, US and WO 2017 / 197056, each of which is incorporated herein by reference in its entirety.

[0309] In certain embodiments, the present invention provides a method for treating a cereblon-associated ubiquitin ligase (LBM) comprising administering to a mammalian subject the invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing a ubiquitin ligase having the structure of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, or I-oo-10, respectively: [ka] or a compound of formula I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I-oo'-9, or I-oo'-10, respectively: [ka] or a compound of formula I-oo''-1, I-oo''-2, I-oo''-3, I-oo''-4, I-oo''-5, I-oo''-6, I-oo''-7, I-oo''-8, I-oo''-9, or I-oo''-10, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables [ka] , X, X1, X2, Y, R1, R3, R3', R4, R5, t, m and n are as defined and described in WO 2017 / 007612 and US 2018 / 0134684, each of which is incorporated by reference in its entirety.

[0310] Thus, in some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] but [ka] and; 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), where Y1 is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene; X is C(O) or C(R3)2; X1-X2 is C(R3)=N or C(R3)2-C(R3)2; each R1 is independently halogen, nitro, NH2, OH, C(O)OH, C1-C6 alkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R2 is halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R2' is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and when R2' is not H, it is halogen, N(R a)2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; Each R3 is independently H or C6-C 10 C1-C3 alkyl optionally substituted with aryl or 5-10 membered heteroaryl; each R3' is independently C1-C3 alkyl; each R4 is independently H or C1-C3 alkyl; or two R4, together with the carbon atoms to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R5 is H, C1-C3 alkyl, F, or Cl; Each R a are independently H or C1-C6 alkyl; R b is H or tosyl; t is 0 or 1; m is 0, 1, 2, or 3; and n is 0, 1 or 2;

[0010] Provided are compounds of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, I-oo-10, I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I-oo'-9, I-oo'-10, I-oo''-1, I-oo''-2, I-oo''-3, I-oo''-4, I-oo''-5, I-oo''-6, I-oo''-7, I-oo''-8, I-oo''-9, or I-oo''-10, or a pharmaceutically acceptable salt thereof.

[0311] In certain embodiments, the present invention provides a method for treating a cereblon-associated HIV-1 / HIV-2 / HIV-3 / HIV-4 / HIV-5 / HIV-6 / HIV-1 / HIV-2 / HIV-3 / HIV-4 / HIV-5 / HIV-6 / HIV-6 HIV-1 / HIV-2 / HIV-3 / HIV-4 / HIV-5 ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables A, G, G', Q1, Q2, Q3, Q4, R, R', W, X, Y, Z, [ka] , and each of n is as defined and described in WO 2016 / 197114 and US 2018 / 0147202, each of which is incorporated by reference in its entirety.

[0312] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0313] In some embodiments, the LBM is selected from those in Table 1 below.

[0314] In some embodiments, the present invention provides a compound represented by formula Ij-1, wherein LBM is thalidomide, and ring P and ring Q form a benzoxazole ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein L, L x , X, R x , R y, each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0315] In some embodiments, the present invention provides a compound represented by formula Ij-3, wherein the LBM is thalidomide, and ring P and ring Q form an indazole ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0316] In some embodiments, the present invention provides a compound represented by formula Ij-4, wherein the LBM is thalidomide, and ring P and ring Q form an imidazo[1,2-a]pyridine ring, as shown: [ka] or a pharmaceutically acceptable salt thereof, wherein L, L x , X, R x , R y , each of ring T, x, and y, both alone and in combination, are as defined above and as described in the embodiments herein.

[0317] In some embodiments, the present invention relates to a method for treating LBM comprising administering to a subject a therapeutically effective amount of thalidomide or [ka] and the ring Q is [ka] and one R xis -OR and X is cyclohexyl and has formula Ik-2 or Ik-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L is as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's x the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] and; Each R z independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring P is selected from benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring P is optionally substituted with 1 to 2 oxo groups; Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; L x is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently selected from the group consisting of -Cy x and optionally replaced by -, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR-, or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR-, or -CR=CR- is R x or R y together with may form a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -Cy x - is an optionally substituted group selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy x - is optionally substituted with 1 to 2 oxo groups; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0318] In certain embodiments, the present invention provides L x is an amide, ring P is pyrazolyl, ring T is pyridyl, R is Me, and R yis —CF 3 .

[0319] In some embodiments, the present invention relates to a method for treating LBM comprising administering to a subject a therapeutically effective amount of thalidomide or [ka] wherein ring P and ring Q form an indazole ring, and one R x is -OR and X is cyclohexyl, and has formula Ik-4 or Ik-5: [ka] or a pharmaceutically acceptable salt thereof, wherein L is as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's x the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] and; Each R z independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; L x is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently selected from the group consisting of -Cy x and optionally replaced by -, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR-, or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR-, or -CR=CR- is R x or R y together with may form a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -Cy x - is an optionally substituted group selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy x - is optionally substituted with 1 to 2 oxo groups; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0320] In certain embodiments, the present invention provides L x is an amide, Ring T is pyridyl, R is Me, and R y is —CF 3 .

[0321] In some embodiments, the present invention relates to a method for treating LBM comprising administering to a subject a therapeutically effective amount of thalidomide or [ka] and the ring Q is [ka] and a, L x is an amide and one R x is -OR and X is cyclohexyl, and has formula Ik-6 or Ik-7: [ka] or a pharmaceutically acceptable salt thereof, wherein L is as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's xthe groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] and; Each R z independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring P is selected from benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring P is optionally substituted with 1 to 2 oxo groups; Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0322] In certain embodiments, the present invention provides a compound in which ring P is pyrazolyl, ring T is pyridyl, R is Me, and R y is —CF 3 .

[0323] In some embodiments, the present invention relates to a method for treating LBM comprising administering to a subject a therapeutically effective amount of thalidomide or [ka] wherein ring P and ring Q form an indazole ring, and L x is an amide and one R x is -OR and X is cyclohexyl and has formula Ik-8 or Ik-9: [ka] or a pharmaceutically acceptable salt thereof, wherein L is as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's x the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] and; Each R z independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring T is selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0324] In certain embodiments, the present invention provides a compound in which Ring T is pyridyl, R is Me, and R y is —CF 3 .

[0325] In some embodiments, the present invention relates to a method for treating LBM comprising administering to a subject a therapeutically effective amount of thalidomide or [ka] wherein ring P and ring Q form an indazole ring, ring T is pyridyl, and L x is an amide and one R x is -OR and X is cyclohexyl, and has formula Ik-10 or Ik-11: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L is as defined and described herein, and Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's x the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] and; Each R z independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each x is 0, 1, 2, 3, or 4; and Each y is 0, 1, 2, 3, or 4.

[0326] In certain embodiments, the present invention provides a compound wherein R is Me and R y is —CF 3 .

[0327] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and the ring Q is [ka] and one R x is -OR and X is cyclohexyl, and has formula Ik-12: [ka] or a pharmaceutically acceptable salt thereof, wherein the variable [ka] , Y, R1, R3, R3', R4, R5, t, m, n, ring P, ring T, L, L x , R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0328] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] and the ring Q is [ka] and one R x is -OR and X is cyclohexyl, and has formula Ik-13: [ka] or a pharmaceutically acceptable salt thereof, wherein variable X 1 , X 2 , X 3 , R 1 , R 2 , ring A, m, ring P, ring T, L, L x , R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0329] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring P and ring Q form an indazole ring, and one R x is -OR and X is cyclohexyl, and has formula Ik-14: [ka] or a pharmaceutically acceptable salt thereof, wherein the variable [ka] , Y, R1, R3, R3', R4, R5, t, m, n, ring T, L, L x , R x , R yEach of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0330] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of LBM, as shown. [ka] wherein ring P and ring Q form an indazole ring, and one R x is -OR and X is cyclohexyl, and has the formula Ik-15: [ka] or a pharmaceutically acceptable salt thereof, wherein variable X 1 , X 2 , X 3 , R 1 , R 2 , ring A, m, ring T, L, L x , R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0331] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula I-qq-1, I-qq-2, or I-qq-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2,X, [ka] and each of n is as defined in WO 2017 / 197051, which is incorporated herein by reference in its entirety; and [ka] is R 1 , R 1 and R 2 or R 17 R as defined in WO 2017 / 197051 12 binding site, resulting in [ka] R 12 It takes the place of a substituent.

[0332] In some embodiments, the present invention provides a method for treating a cereblon-associated ubiquitin ligase (LBM) comprising administering to a mammalian subject the present invention an LBM comprising an LBM having the formula I-rr-1, I-rr-2, I-rr-3, or I-rr-4, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 ,X, [ka] and each of n is as defined in WO 2018 / 237026, each of which is incorporated by reference herein in its entirety; and [ka] is R 1 or R 16 R as defined in WO 2018 / 237026 12 binding site, resulting in [ka] R 12 It takes the place of a substituent.

[0333] In some embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein (FBG) comprising administering to a subject therapies a method for treating a fibronectin-binding protein (FOF ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 1 , R 14 , and R 16 each as defined in WO 2018 / 237026, each of which is incorporated by reference herein in its entirety; and [ka] is R 1 or R 16 R as defined in WO 2018 / 237026 12 binding site, resulting in [ka] R 12 It takes the place of a substituent.

[0334] In certain embodiments, the present invention provides an LBM that is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula I-tt-1, I-tt-2, I-tt-3, I-tt-4, I-tt-5, I-tt-6, I-tt-7, or I-tt-8: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, L, x, y, and [ka] each as described and defined in WO 2017 / 161119, each of which is incorporated by reference herein in its entirety.

[0335] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and each of the variables A, B, C, W, X, Y, and Z are as described and defined in U.S. Pat. No. 5,721,246, each of which is incorporated herein by reference in its entirety.

[0336] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, such as represented by formula I-vv: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and each of the variables R1, R2, and n is as described and defined in WO 2019 / 043214, each of which is incorporated herein by reference in its entirety.

[0337] In some embodiments, the LBM comprises an IAP E3 ubiquitin ligase binding moiety as described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4):669-81, e.g., [ka] [ka] where [ka] is attached to a modifiable carbon atom, oxygen atom, nitrogen atom, or sulfur atom.

[0338] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety having the formula I-ww-1, I-ww-2, I-ww-3, I-ww-4, or I-ww-5, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R 1’ , R 2’ , R 3’Each of X, X, and X' is as defined and described in WO 2013 / 106643 and US 2014 / 0356322, each of which is incorporated by reference herein in its entirety.

[0339] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety having formula I-xx-1, I-xx-2, I-xx-3, I-xx-4, I-xx-5, or I-xx-6, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable 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, Z1, Z2, Z3, Z4, and o are as defined and described in WO 2016 / 149668 and US 2016 / 0272639, each of which is incorporated by reference in its entirety.

[0340] As used herein, the bracket description surrounding any LBM [ka] is this [ka] This means that the moiety is covalently attached to the LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For clarity, by way of example, such available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structures are illustrated below, where each wavy bond represents the [ka] Specifies the attachment point to: [ka] .

[0341] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety of formula I-yy-1, I-yy-2, or I-yy-3, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R p , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 Each of 1, 2, and 3 is as defined and described in WO 2016 / 118666 and US 2016 / 0214972, each of which is incorporated by reference in its entirety.

[0342] In certain embodiments, the present invention provides that the LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety, thereby having formula I-zz-1, I-zz-2, I-zz-3, I-zz-4, I-zz-5, I-zz-6, or I-zz-7, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and variable A 1 , A 2 , A 3 , R 5 , G and Z are as defined and described in WO 2017 / 176958.

[0343] In certain embodiments, the present invention provides a method for the preparation of CRBN E3 ubiquitin ligase-binding moieties, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is represented by the formula I-zz'-1, I-zz''-1, I-zz'-2, I-zz'-2, I-zz'-3, I-zz''-3, I-zz'-4, I-zz''-4, I-zz'-7, or I-zz''-7, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and variable A 1 , A 2 , A 3 , R 5, G and Z are each as defined and described in WO 2017 / 176958, which is incorporated by reference in its entirety.

[0344] In certain embodiments, the present invention provides that the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby representing a sequence of formula I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, or I-aaa-18, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R 6’, R 7’ , R 8’ , R 9’ , R 10’ , R 11’ , R 12’ , R 1’’ , A, A', A'', X, Y, and Z are as defined and described in WO 2017 / 011371 and US 2017 / 0008904, each of which is incorporated by reference in its entirety.

[0345] In certain embodiments, the present invention provides an IAP E3 ubiquitin ligase binding moiety, whereby the LBM is an IAP E3 ubiquitin ligase binding moiety having the formula I-bbb-1, I-bbb-2, I-bbb-3, or I-bbb-4, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each as defined and described in WO 2017 / 011590 and US 2017 / 0037004, each of which is incorporated by reference in its entirety.

[0346] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; thereby having the formula I-ccc-1, I-ccc-2, or I-ccc-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and X 1 , X 2a , and X 3a each independently represents a covalent bond, —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 4a and X 5a each independently is —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; R 2 , R 3b , and R 4a each independently represents 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)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 or C 1~6 It is aliphatic; Each R 6 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A a is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or an 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring C a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0347] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula I-ccc'-1 or I-ccc''-1: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, ring A, a , X 1 , X 2a , X 3a , R 1 , R 2 and m is as described above.

[0348] X, as defined above and described herein; 1 , X 2a , and X 3a each independently represents a covalent bond, —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from

[0349] In some embodiments, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0350] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0351] In some embodiments, X 2a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0352] In some embodiments, X 2a is selected from those illustrated in Table 1 below.

[0353] In some embodiments, X 3a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0354] In some embodiments, X 3a is selected from those illustrated in Table 1 below.

[0355] X, as defined above and described herein; 4 and X 5 each independently is —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from

[0356] In some embodiments, X 4a is -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0357] In some embodiments, X 4a is selected from those illustrated in Table 1 below.

[0358] In some embodiments, X 5a is -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0359] In some embodiments, X 5a is selected from those illustrated in Table 1 below.

[0360] R as defined above and described herein 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic.

[0361] In some embodiments, R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic.

[0362] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0363] R as defined above and described herein 2 , R 3b , and R 4a each independently represents 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0364] In some embodiments, R 2 is 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0365] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0366] In some embodiments, R 3b is 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0367] In some embodiments, R 3b is methyl.

[0368] In some embodiments, R 3b is selected from those illustrated in Table 1 below.

[0369] In some embodiments, R 4a is 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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0370] In some embodiments, R 4a is methyl.

[0371] In some embodiments, R 4a is selected from those illustrated in Table 1 below.

[0372] R as defined above and described herein 5a is hydrogen or C 1~6 It is aliphatic.

[0373] In some embodiments, R 5a is t-butyl.

[0374] In some embodiments, R 5a is selected from those illustrated in Table 1 below.

[0375] As defined above and described herein, each R 6 independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0376] In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0377] In some embodiments, R6 is selected from those illustrated in Table 1 below.

[0378] Ring A, as defined above and described herein a is a fused ring selected from a 6-membered aryl containing 0 to 2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0379] In some embodiments, ring A a is a fused 6-membered aryl containing 0 to 2 nitrogen atoms. a is a fused 5- to 7-membered partially saturated carbocyclyl. a is a fused 5- to 7-membered partially saturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a is a fused 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0380] In some embodiments, ring A a is a fused phenyl.

[0381] In some embodiments, ring A a is selected from those illustrated in Table 1 below.

[0382] Ring B, as defined above and described herein a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or an 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0383] In some embodiments, ring B ais a 6-membered aryl containing 0 to 2 nitrogen atoms. a is an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0384] In some embodiments, ring B a teeth, [ka] is.

[0385] In some embodiments, ring B a is selected from those illustrated in Table 1 below.

[0386] As defined above and described herein, ring C a is selected from a 6-membered aryl containing 0 to 2 nitrogen atoms or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0387] In some embodiments, ring C a is a 6-membered aryl containing 0 to 2 nitrogen atoms. In some embodiments, ring C a is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0388] In some embodiments, ring C a teeth, [ka] is.

[0389] In some embodiments, ring C a is selected from those illustrated in Table 1 below.

[0390] As defined above and described herein, m is 0, 1, 2, 3, or 4.

[0391] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0392] In some embodiments, m is selected from those depicted in Table 1 below.

[0393] In some embodiments, o is selected from those depicted in Table 1 below.

[0394] As defined above and described herein, o is 0, 1, 2, 3, or 4.

[0395] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0396] In some embodiments, o is selected from those depicted in Table 1 below.

[0397] As defined above and described herein, q is 0, 1, 2, 3, or 4.

[0398] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0399] In some embodiments, q is selected from those depicted in Table 1 below.

[0400] As defined above and described herein, each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen atom, optionally taken together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0401] In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen atom, optionally together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0402] In some embodiments, R is selected from those depicted in Table 1 below.

[0403] In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has the formula I-ddd: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables R, R 10 , R 11 , R 14a , and R 15 each as described and defined in WO 2017 / 030814, WO 2016 / 118666, and US 2017 / 0327469, each of which is incorporated by reference in its entirety.

[0404] In certain embodiments, the present invention provides a method for treating a VHL-associated steroid deficiency, wherein the LBM is a VHL binding moiety, whereby the LBM has the formula I-eee-1 or I-eee-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and variables X, W, R, R 10 , R 11 , R 14a , and R 14b , R 15 , R 16 Each of , and o is as described and defined in WO 2017 / 030814, WO 2016 / 118666, and US 2017 / 0327469, each of which is incorporated by reference in its entirety.

[0405] In certain embodiments, the present invention provides a method for treating a leukemia where the LBM is an IAP binding moiety, whereby the LBM has the formula I-fff: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables W, Y, Z, R 1 , R 2 , R 3, R 4 , and R 5 each as described and defined in WO 2014 / 044622, US 2015 / 0225449, WO 2015 / 071393, and US 2016 / 0272596, each of which is incorporated by reference in its entirety.

[0406] In certain embodiments, the present invention provides a method for treating MDM2 comprising administering to a subject an LBM comprising administering to a subject an LBM, the method ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and as described and defined in Hines, J. et al., Cancer Res. (DOI: 10.1158 / 0008-5472.CAN-18-2918), each of which is incorporated by reference in its entirety.

[0407] In certain embodiments, the present invention provides a method for treating a DCAF16-binding moiety, the method comprising administering to a subject a subject therapies comprising administering to a subject a compound of formula I-hhh: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and as described and defined in Zhang, X. et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 443804), each of which is incorporated herein by reference in its entirety.

[0408] In certain embodiments, the present invention provides a compound wherein the LBM is an RNF114 binding moiety, whereby the compound has formula I-iii: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and as described and defined in Spradin, JNet al., bioRxiv (doi: https: / / doi.org / 10.1101 / 436998), each of which is incorporated herein by reference in its entirety.

[0409] In certain embodiments, the present invention provides a compound wherein the LBM is an RNF4 binding moiety, whereby the compound has formula I-jjj: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and as described and defined in Ward, CC, et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125), each of which is incorporated herein by reference in its entirety.

[0410] In certain embodiments, the present invention provides a method for treating a VHL-binding moiety, the method comprising administering to a patient a compound of formula I-nnn-1 or I-nnn-2: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R 1 , R 2 , R 3 , X, and Y are each as defined and described in WO 2019 / 084026, each of which is incorporated by reference in its entirety.

[0411] In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has formula I-ooo-1 or I-ooo-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R 1 , R 3 and Y are each as defined and described in WO 2019 / 084030, each of which is incorporated by reference in its entirety.

[0412] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, thereby providing a ubiquitin ligase having the formula I-ppp-1, I-ppp-2, I-ppp-3, or I-ppp-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 and each of X is as defined in WO 2019 / 099868, the entire contents of which are incorporated herein by reference; and [ka] is R 17 or R 16 R as defined in WO 2018 / 237026 12 binding site, resulting in [ka] R 12 It takes the place of a substituent.

[0413] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0414] In certain embodiments, the present invention provides a method for treating a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety of formula I-qqq: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and wherein: each X 1 are independently -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] and; X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] and; Z 1 and Z 2 are independently a carbon atom or a nitrogen atom; Ring A is a fused ring selected from a 4- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from benzo, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-; Each R 1 are independently hydrogen, deuterium, R 4, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CF2R, —CR2F, —CF3, —CR2(OR), —CR2(NR2), —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —C(S)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, —Si(OR)R2, and —SiR3; or 2 R's 1 the groups optionally taken together form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently selected from hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2 teeth, [ka] or hydrogen; Ring B is phenyl, a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is further optionally substituted with 1 to 2 oxo groups; Each R 3 are independently hydrogen, deuterium, R 4 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(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, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, and -SiR3; Each R 4 independently, C 1~6 selected from optionally substituted groups selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [ka] is a single or double bond; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4; and o is 0, 1, or 2.

[0415] As defined above and described herein, each X 1 are independently a covalent bond, -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] is.

[0416] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 is —O—. In some embodiments, X 1 is -NR-. In some embodiments, X 1 In some embodiments, X is —CF—. 1 teeth [ka] In some embodiments, X 1 is —C(O)—. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 teeth [ka] is.

[0417] In certain embodiments, X 1 is selected from those shown in the compounds of Table 1.

[0418] X, as defined above and described herein; 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0419] In some embodiments, X 2and X 3 is independently -CH-. In some embodiments, X 2 and X 3 is independently —C(O)—. In some embodiments, X 2 and X 3 is independently -C(S)-. In some embodiments, X 2 and X 3 is independent, [ka] is.

[0420] In certain embodiments, X 2 and X 3 are independently selected from those shown in the compounds of Table 1.

[0421] X, as defined above and described herein; 4 is a covalent bond, -CH2-, -CR2-, -O-, -NR-, -CF2-, [ka] is.

[0422] As defined above and described herein, Z 1 and Z 2 are independently carbon atoms or nitrogen atoms.

[0423] In some embodiments, Z 1 and Z 2 are independently carbon atoms. In some embodiments, Z 1 and Z 2 are independently carbon atoms.

[0424] In certain embodiments, Z 1 and Z 2 are independently selected from those shown in the compounds of Table 1.

[0425] As defined above and described herein, Ring A is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0426] In some embodiments, ring A is benzo. In some embodiments, ring A is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0427] In certain embodiments, ring A is selected from those shown in the compounds of Table 1.

[0428] As defined above and described herein, L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0429] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0430] In some embodiments, L 1 is -C(O)-.

[0431] In certain embodiments, L 1 is selected from those shown in the compounds of Table 1.

[0432] As defined above and described herein, each R 1 are independently hydrogen, deuterium, R 4 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3, or two R 1 The groups optionally taken together form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0433] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is R 4 In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is —NO. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -NR2. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)NR. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1is -CF2R. In some embodiments, R 1 is —CF. In some embodiments, R 1 is -CR2(OR). In some embodiments, R 1 is -CR2(NR2). In some embodiments, R 1 is —C(O)R. In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1 is —C(O)NR. In some embodiments, R 1 is —C(O)N(R)OR. In some embodiments, R 1 is -OC(O)R. In some embodiments, R 1 is —OC(O)NR. In some embodiments, R 1 is —C(S)NR. In some embodiments, R 1 is —N(R)C(O)OR. In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)NR. In some embodiments, R 1 is —N(R)S(O)R. In some embodiments, R 1 is -OP(O)R. In some embodiments, R 1 is -OP(O)(OR). In some embodiments, R 1 is -OP(O)(OR)NR. In some embodiments, R 1 is -OP(O)(NR). In some embodiments, R 1 is —Si(OR)R. In some embodiments, R 1 is -SiR. In some embodiments, two R 1 The groups optionally taken together form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0434] In certain embodiments, each R 1 are independently selected from those shown in the compounds of Table 1.

[0435] As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group, which optionally substituted group is C 1~6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally taken together with the atoms between them form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0436] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen, together with atoms between them, optionally form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0437] R as defined above and described herein2 teeth, [ka] or hydrogen.

[0438] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is hydrogen.

[0439] In certain embodiments, R 2 is selected from those shown in the compounds of Table 1.

[0440] As defined above and described herein, Ring B is phenyl, a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is further optionally substituted with 1 to 2 oxo groups.

[0441] In some embodiments, ring B is phenyl. In some embodiments, ring B is a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is further optionally substituted with 1 to 2 oxo groups.

[0442] In certain embodiments, ring B is selected from those shown in the compounds of Table 1.

[0443] As defined above and described herein, each R 3 are independently hydrogen, deuterium, R 4 , halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CF2R, —CF3, —CR2(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, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, and —SiR3.

[0444] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is R 4 In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is -NR2. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -CF2R. In some embodiments, R 3 is —CF. In some embodiments, R 3 is -CR2(OR). In some embodiments, R 3is -CR2(NR2). In some embodiments, R 3 is —C(O)R. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3 is —C(O)N(R)OR. In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is —OC(O)NR. In some embodiments, R 3 is —N(R)C(O)OR. In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)NR. In some embodiments, R 3 is —N(R)S(O)R. In some embodiments, R 3 is -OP(O)R. In some embodiments, R 3 is -OP(O)(OR). In some embodiments, R 3 is -OP(O)(OR)NR. In some embodiments, R 3 is -OP(O)(NR). In some embodiments, R 3 is -SiR3.

[0445] In certain embodiments, R 3 is selected from those shown in the compounds of Table 1.

[0446] As defined above and described herein, each R 4 independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0447] In some embodiments, R 4 is replaced by C 1~6 In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0448] In certain embodiments, R 4 is selected from those shown in the compounds of Table 1.

[0449] As defined above and described herein, [ka] is a single or double bond.

[0450] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0451] In certain embodiments, [ka] is selected from those shown in the compounds of Table 1.

[0452] As defined above and described herein, m is 0, 1, 2, 3, or 4.

[0453] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0454] In certain embodiments, m is selected from those shown in the compounds of Table 1.

[0455] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0456] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0457] In certain embodiments, n is selected from those shown in the compounds of Table 1.

[0458] As defined above and described herein, o is 0, 1, or 2.

[0459] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 2.

[0460] In certain embodiments, o is selected from those shown in the compounds of Table 1.

[0461] In some embodiments, the present invention provides a compound as shown, wherein ring A is benzo, o is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2is a carbon atom and has formula I-qqq-1: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, L 1 , R 1 , R 2 Each of , and m, both alone and in combination, is as defined above and as described in embodiments herein.

[0462] In some embodiments, the present invention provides a compound as shown, wherein ring A is benzo, o is 1, and X 1 , X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom and has formula I-qqq-12: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, L 1 , R 1 , R 2 Each of , and m, both alone and in combination, is as defined above and as described in embodiments herein.

[0463] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0464] In some embodiments, the LBM is selected from those in Table 1 below.

[0465] In certain embodiments, the present invention provides a compound wherein the LBM is an RPN13 binding moiety, whereby the compound has the formula I-rrr: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and each of the variables A, Y, and Z are as described and defined in WO 2019 / 165229, each of which is incorporated herein by reference in its entirety.

[0466] In certain embodiments, the present invention provides a method for producing a Ubr1-binding moiety, wherein the LBM is a Ubr1-binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074 / jbc.AC119.010790, each of which is incorporated by reference herein in its entirety, whereby the LBM is a Ubr1-binding moiety of formula I-sss-1 or I-sss-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein.

[0467] In certain embodiments, the present invention provides a method for treating a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety of formula I-uuu-1, I-uuu-2, I-uuu-3, or I-uuu-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variables Y, A 1 , and A 3 each as described and defined in WO 2019 / 236483, each of which is incorporated by reference in its entirety.

[0468] In a specific embodiment, the present invention provides a method for the preparation of a polypeptide comprising the LBM of formula I-vvv: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK, both alone and in combination, are as defined above and as described in embodiments herein.

[0469] In certain embodiments, the present invention provides a method for treating a KEAP1-associated leukemia (LBM) comprising administering to a mammalian subject the invention, wherein the LBM is a KEAP1-binding moiety as described in Lu et al., Euro. J. Med. Chem., 2018, 146:251-9, whereby the LBM has the formula I-www: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK, both alone and in combination, are as defined above and as described in embodiments herein.

[0470] In certain embodiments, the present invention provides a compound wherein the LBM is a KEAP1-NRF2 binding moiety, whereby the compound has formula I-xxx or I-xxx-2: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and in embodiments herein, and each of the variables R, R1, R5, and R8 are as described and defined in WO 2020 / 018788, each of which is incorporated by reference in its entirety.

[0471] In certain embodiments, the present invention provides a compound having the formula I-yyy-1 or I-yyy-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK, both alone and in combination, are as defined above and as described in embodiments herein.

[0472] In some embodiments, the present invention provides a method for detecting an LBM comprising administering to a mammalian subject the method ... [ka] whereby the compound of formula I-zzz-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L, L x , X, ring P, ring Q, ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0473] In some embodiments, the present invention provides a method for detecting a DCAF15 E3 ubiquitin ligase (LBM). [ka] whereby the compound of formula I-zzz-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L, L x , X, ring P, ring Q, ring T, R x , R y Each of x, and y, both alone and in combination, is as defined above and as described in embodiments herein.

[0474] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] is.

[0475] Lysine mimics In some embodiments, the DIM is an LBM as described above and herein. In some embodiments, the DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to a member of the IRAK kinase family (i.e., IRAK-1, -2, -3, or -4) is achieved by the action of a lysine mimetic. In some embodiments, when a compound of Formula I binds to IRAK-1, the lysine mimetic moiety causes ubiquitination, thereby marking IRAK-1 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-2, the lysine mimetic moiety causes ubiquitination, thereby marking IRAK-2 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-3, the lysine mimetic moiety undergoes ubiquitination, thereby marking IRAK-3 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-4, the lysine mimetic moiety undergoes ubiquitination, thereby marking IRAK-4 for degradation via the ubiquitin-proteasome pathway (UPP).

[0476] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] is.

[0477] In some embodiments, the DIM is selected from those depicted in Table 1 below.

[0478] In certain embodiments, the present invention provides a method for treating rhodamine-containing ... [ka] which gives the formula I-kkk-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of IRAK and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0479] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a therapeutically effective amount of DIM. [ka] which gives the formula I-kkk-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of IRAK and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0480] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a therapeutically effective amount of DIM. [ka] which gives the formula I-kkk-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of IRAK and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0481] In certain embodiments, the present invention provides a method for treating rhodamine-containing ... [ka] which give the compounds of formula I-lll-1, I-lll-2, or I-lll-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein, and the variable R 1 , R 4 , R 5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496, the entirety of each of which is incorporated herein by reference.

[0482] hydrogen atom In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent attachment of ubiquitin to one or more members of the IRAK family (i.e., IRAK-1, -2, -3, or -4) is achieved by provided compounds in which DIM is a hydrogen atom. In some embodiments, when a compound of Formula I binds to IRAK-1, the DIM that is hydrogen achieves ubiquitination, thereby marking IRAK-1 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-2, the DIM that is hydrogen achieves ubiquitination, thereby marking IRAK-2 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-3, the DIM that is hydrogen achieves ubiquitination, thereby marking IRAK-3 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula I binds to IRAK-4, the hydrogen DIM effects ubiquitination, thereby marking IRAK-4 for degradation via the ubiquitin-proteasome pathway (UPP).

[0483] In some embodiments, the DIM is selected from those depicted in Table 1 below.

[0484] In some embodiments, the present invention provides compounds wherein DIM is a hydrogen atom, thereby providing compounds of the formula I-mmm: [ka] or a pharmaceutically acceptable salt thereof, wherein each of IRAK and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0485] Linker (L) As defined above and described herein, L is a bivalent moiety that links IRAK to LBM or IRAK to DIM.

[0486] In some embodiments, L is a bivalent moiety that binds IRAK to LBM. In some embodiments, L is a bivalent moiety that binds IRAK to DIM. In some embodiments, L is a bivalent moiety that binds IRAK to a lysine mimetic.

[0487] In some embodiments, L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D)2-, -CRF-, -CF2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, [ka] wherein each -Cy- is independently phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted divalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and R is as described above (e.g., in Formula Ia).

[0488] In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0489] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] is.

[0490] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] is.

[0491] In some embodiments, the optionally substituted groups on -Cy- are -F, -C 1~6 Alkyl, -OH, -OC 1~6 Alkyl, -CO2H, -CO2C 1~6Alkyl, -(CH2) 1~6 CO2H, -(CH2) 1~6 CO2C 1~6 Alkyl, -P(O)(OH)2, -P(O)(OC 1~6 alkyl)2, -(CH2) 1~6 P(O)(OH)2, and -(CH2) 1~6 P(O)(OC 1~6 alkyl)2.

[0492] In some embodiments, -Cy- is selected from those depicted in Table 1 below.

[0493] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9...

Claims

1. Formula: 【Chemistry 2071】 or a pharma- ceutically acceptable salt thereof, having the formula: HET is a heteroaryl selected from indolyl, pyrrolo[1,2-b]pyridazine, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, wherein said heteroaryl is substituted with R a and R b ; R a is H, F, Cl, Br, -CN, -OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 1-4 hydroxyalkyl), -NH(C 1-4 fluoroalkyl), -NH(C 1-6 hydroxy-fluoroalkyl), -CH 2 NHC(O)(C 1-6 alkyl), -CH 2 NHC(O)(C 1-6 hydroxyalkyl), -CH 2 NHC(O)NH(C 1-6 alkyl), -CH 2 NHC(O)NHCH 2 (phenyl), -CH 2 NHC(O)N(C 1-4 alkyl) 2 , -CH 2 NHC(O)O(C 1-4 alkyl), -CH 2 NHC(O)(C 3-6 cycloalkyl), -CH 2 NHC(O)(tetrahydrofuranyl), -CH 2 NHC(O)CH 2 (C 3-6 cycloalkyl), -CH 2 NHC(O)CH 2 (tetrahydropyranyl), -CH 2 NHC(O)CH 2 (phenyl), -NHC(O)(C 1-4 alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl; R b is H or —NH 2 ; R 1 is (i) C1-6 alkyl, C1-6 alkylC3-6 cycloalkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-8 hydroxy-fluoroalkyl, -(C1-6 alkylenyl)O(C1-4 alkyl), -(C1-6 alkylenyl)O(C1-4 fluoroalkyl), -(C1-6 fluoroalkylenyl)O(C1-4 alkyl), -(C1-6 fluoroalkylenyl)O(C1-4 deuteroalkyl), -(C1-fluoroalkylenyl)O(C1-4 fluoroalkyl), -(C1-4 fluoroalkylenyl)C(C3-6 cycloalkyl)2(OH), -(C1-4 alkylenyl)NHC(O)(C1-4 alkylenyl)OC(O)(C 1-3 alkyl), -(C 1-6 alkylenyl)NHS(O) 2 (C 1-4 alkyl), -(C 1-6 alkylenyl)P(O)(C 1-4 alkoxy) 2 , -(C 1-6 fluoroalkylenyl)NH(C 1-4 alkyl), -(C 1-6 alkylenyl)C(O)NH(C 1-4 alkyl), -(C 1-6 fluoroalkylenyl)C(O)NH(C 1-4 alkyl), -(C 1-6 fluoroalkylenyl)C(O)NH(C 1-4 hydroxyalkyl), or -(C 1-6 fluoroalkylenyl)OP(O)(OH) 2 ; (ii) -(C1-3 alkylenyl)Rx, -(C1-3 fluoroalkylenyl)Rx, -(C1-3 alkylenyl)C(O)Rx, -(C1-3 alkylenyl)C(O)NHRx, -(C1-3 fluoroalkylenyl)C(O)Rx, or -CH2CF=(tetrahydropyranyl), where Rx is a cyclic group selected from C3-6 cycloalkyl, 1,1-dioxidothiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, where each cyclic group is selected from F, -OH, -CH3, -C(CH2)2OH, -OCH3, -C(O)CH2 substituted with 0 to 3 substituents independently selected from CN, -S(O)2CH3, -S(O)2NH2, -NHC(O)CH3, -N(S(O)2CH3)2, oxetanyl, and morpholinyl; (iii) C 3-6 cycloalkyl or C 4-6 cycloalkenyl, each of which is F, —OH, —CN, C 1-3 alkyl, C 1-3 alkoxy, —S(C 1-3 alkyl), —NO 2 , —S(O) 2 (C 1-3 alkyl), C 1-4 hydroxyalkyl, —C(C 1-3 alkyl)(OH)(C 3-6 cycloalkyl), —CH 2 C(O)NH(C 1-3 alkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(C 1-4 hydroxyalkyl), —C(O)NH(C 1-3 alkyl), —C(O)NH(C 1-3 deuteroalkyl), —C(O)NH(C 3-6 cycloalkyl), —NHC(O)O(C 1-3 substituted with 0 to 3 substituents independently selected from -NHS(O) 2 (C 1-3 alkyl); or (iv) tetrahydropyranyl or piperidinyl, each of which is substituted with 0 to 1 substituents selected from -OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, and C1-3 alkoxy; and R 2 is (i) C 1-7 alkyl or C 2-6 alkenyl, each of which is substituted with 0 to 3 substituents independently selected from F, -OH, and -CN; -(C 1-4 alkylenyl)O(C 1-4 alkyl), -(C 1-4 alkylenyl)O(C 1-4 fluoroalkyl), -(C 1-6 alkylenyl)NH 2 , -(C 1-6 alkylenyl)S(O) 2 (C 1-3 alkyl), -(C 1-6 fluoroalkylenyl)NH(C 1-3 alkyl), or -(C 1-6 alkylenyl)NHC(O)(C 1-4 fluoroalkyl); (ii) -(Ci_4 alkylenyl)Ry, where Ry is C3_6 cycloalkyl, azetidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl, each of which is substituted with 0 to 2 substituents independently selected from F, -OH, and C1_3 alkyl; or (iii) C3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each of which is F, —OH, C1-3 alkyl, C1-3 hydroxyalkyl, —C(O)(C1-3 alkyl), —C(O)(C1-3 fluoroalkyl), —C(O)(C1-3 cyanoalkyl), —C(O)O(C1-3 alkyl), —C(O)NH2, —C(O)NH(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —NH(C1-3 fluoroalkyl), —NH(oxetanyl), —NHC(O)(C1-3 alkyl), —NHC(O)(C1-3 fluoroalkyl), —NHC(O)(C1-3 fluoroalkyl). 3-6 cycloalkyl), and -S(O) 2 (C 1-3 alkyl); and L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １～５０ A hydrocarbon chain, wherein the 0 to 4 methylene units of L are independently -Cy-, -O-, -N(R)-, -Si(R), ２ -, -Si(OH)(R)-, -Si(OH) ２ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ２ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -S(O) ２ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, 【2006】 is replaced by, where Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bivalent ring selected from an 8- to 10-membered saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R is independently selected from hydrogen, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, optionally taken together with atoms between them, form a 4- to 11-membered, saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having, in addition to said atom, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and LBM, (i) 【Chemistry 2072】 or a pharma- ceutically acceptable salt thereof, in formula I-aa: X １ は, shared combination, -CH ２ -, -CHCF ３ -, -SO ２ -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR ２ -, -C (O) -, -C (S) -, または 【2010】 is a divalent moiety selected from X ２ is a carbon atom or a silicon atom; X ３ is -CR ２ -, -NR-, -O-, -S-, or -Si(R ２ )-; R １ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ２ R, -N(R) ２ , -P(O)(OR) ２ , -P(O)(NR ２ )OR, -P(O)(NR ２ ) ２ , -Si(OH) ２ R, -Si(OH)(R) ２ , -Si(R) ３ , or C １～４ is aliphatic; Each R ２ are independently hydrogen, R ６ , halogen, -CN, -NO ２ , -OR, -SR, -N(R) ２ , -Si(R) ３ , -S(O) ２ R, -S(O) ２ N (R) ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ２ , -C(O)N(R)OR, -C(R) ２ N(R)C(O)R, -C(R) ２ N(R)C(O)N(R) ２ , -OC(O)R, -OC(O)N(R) ２ , -OP(O)R ２ , -OP(O)(OR) ２ , -OP(O)(OR)(NR ２ ), -OP(O)(NR ２ ) ２ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ２ , -NP(O)R ２ , -N(R)P(O)(OR) ２ , -N(R)P(O)(OR)(NR ２ ), -N(R)P(O)(NR ２ ) ２ or -N(R)S(O) ２ R; Ring A is 【Chemistry 2073】 【Chemical 2074】 is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ３ is hydrogen, halogen, -OR, -N(R) ２ or -SR; Each R ４ are independently hydrogen, R ６ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. 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) ２ R; Each R ６ is independent, C １～６ 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L １ is a covalent bond, or C １～３ wherein one to two methylene units of the chain are independently selected from -O-, -C(O)-, -C(S)-, -C(R ... ２ -, -CH(R)-, -C(F) ２ -, -N(R)-, -S-, -S(O) ２ optionally replaced by - or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen, C １～６ or selected from: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (ii) 【Chemistry 2075】 or a pharma- ceutically acceptable salt thereof, in the formula I-nn: Ring M is 【Chemistry 2076】 Selected from: X4 is 【Chemistry 2077】 is a trivalent moiety selected from each R is independently selected from hydrogen, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3a is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 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, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 R; each R 6 is independently selected from C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R 7 is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH)R 2 , -Si(OH) 2 R, -SiR 3 , or a C 1-4 aliphatic; Ring D is selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is a covalent bond or a C 1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain in which one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 -, or -(C)═CH-; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; A compound or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein HET is a heteroaryl selected from indolyl, pyrrolo[1,2-b]pyridazine, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and imidazo[4,5-b]pyridinyl.

3. The compound of claim 1 or claim 2, or a pharma- ceutically acceptable salt thereof, wherein R a is H, F, Cl, -CN, -OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, or C 1-4 alkoxy.

4. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein R b is H.

5. R 1 is (i) C 1-6 alkyl, C 1-6 alkyl C 3-6 cycloalkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, or C 1-8 hydroxy-fluoroalkyl; (ii) C 3-6 cycloalkyl substituted with 0 to 3 substituents independently selected from F, —OH, —CN, C 1-3 alkyl, and C 1-3 alkoxy; or (iii) tetrahydropyranyl or piperidinyl, each of which is substituted with 0 to 1 substituents selected from -OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, and C1-3 alkoxy; 3. The compound of claim 1 or claim 2, wherein:

6. R 2 is (i) C 1-7 alkyl, substituted with 0 to 3 substituents independently selected from F, -OH, and -CN; or (ii) C 3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each of which is substituted with 0 to 3 substituents independently selected from F, —OH, C 1-3 alkyl, and C 1-3 hydroxyalkyl; 3. The compound of claim 1 or claim 2, wherein: 【Request 7】 【Chemical 2078】 but, 【Chemical 2079】 【2080】 3. The compound of claim 1 or claim 2, wherein:

8. Ring A is 【Chemistry 2081】 3. The compound of claim 1 or claim 2, wherein:

9. The compound of claim 1 or claim 2, or a pharma- ceutically acceptable salt thereof, wherein ring B is a fused 6-membered aryl.

10. Ring M is 【Chemistry 2082】 3. The compound of claim 1 or claim 2, wherein:

11. The compound of claim 1 or claim 2, or a pharma- ceutically acceptable salt thereof, wherein Ring D is a 6- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

12. The LBM, 【Chemistry 2083】 【Chemistry 2084】 3. The compound of claim 1 or claim 2, wherein:

13. The LBM, 【Chemistry 2085】 3. The compound of claim 1 or claim 2, wherein:

14. L is a divalent, saturated or unsaturated, linear or branched C １～３０ A hydrocarbon chain, wherein the 0 to 4 methylene units of L are independently -Cy-, -O-, -N(R)-, -Si(R), ２ -, -Si(OH)(R)-, -Si(OH) ２ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ２ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -S(O) ２ 3. The compound of claim 1 or claim 2, wherein the compound is replaced by N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-, or a pharma- ceutically acceptable salt thereof.

15. -Cy- is 【Chemistry 2086】 3. The compound of claim 1 or claim 2, wherein:

16. The compound is 【Chemistry 2087】 【Chemistry 2088】 【Chemistry 2089】 【Chemistry 2090】 【Chemistry 2091】 【Chemistry 2092】 【Chemistry 2093】 3. The compound of claim 1 or claim 2, selected from: or a pharma- ceutically acceptable salt thereof.

17. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

18. A method for degrading and / or inhibiting IRAK4 protein kinase in a patient or biological sample, comprising administering to the patient or contacting with the biological sample a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

19. 17. A method of treating a disorder, disease, or condition mediated by IRAK4 in a patient, comprising administering to the patient a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

20. The method of claim 19, wherein the disorder, disease or condition mediated by IRAK4 is selected from the group consisting of cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

21. The cancer or proliferative disorder may be a benign or malignant tumor of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, solid tumor, carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, colon cancer, colorectal adenoma, head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia. diseases, neoplasms, neoplasms of epithelial character, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung carcinomas, lymphomas, Hodgkin's or non-Hodgkin's lymphomas, breast cancer, follicular carcinomas, undifferentiated carcinomas, papillary carcinomas, seminomas, melanomas, IL-1 driven disorders, MyD88 driven disorders, smoldering or indolent multiple myelomas, and leukemias, diffuse large B cell lymphomas (DLBCL), ABC 21. The method of claim 20, wherein the hematological malignancy is selected from the group consisting of DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma.

22. The inflammatory disorders include systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, anterior uveitis, posterior uveitis, Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. inflammation, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic, nonallergic, mild, moderate, severe, bronchitis or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia Hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymis inflammation, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,21. The method of claim 20, wherein the disease is selected from the group consisting of paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

23. 20. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for degrading and / or inhibiting IRAK4 protein kinase in a patient or biological sample.

24. 20. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disorder, disease, or condition mediated by IRAK4 in a patient.

25. The use of claim 24, wherein the disorder, disease or condition mediated by IRAK4 is selected from the group consisting of cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

26. The cancer or proliferative disorder may be a benign or malignant tumor of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, solid tumor, carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, colon cancer, colorectal adenoma, head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia. diseases, neoplasms, neoplasms of epithelial character, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung carcinomas, lymphomas, Hodgkin's or non-Hodgkin's lymphomas, breast cancer, follicular carcinomas, undifferentiated carcinomas, papillary carcinomas, seminomas, melanomas, IL-1 driven disorders, MyD88 driven disorders, smoldering or indolent multiple myelomas, and leukemias, diffuse large B cell lymphomas (DLBCL), ABC 26. The use of claim 25, wherein the hematological malignancies are selected from the group consisting of DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma.

27. The inflammatory disorders include systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, anterior uveitis, posterior uveitis, Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathies, and systemic juvenile idiopathies. arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy as appropriate), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma, acute lung injury, acute respiratory distress Syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epidermal growth factor receptors, Condylaritis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris,26. The use according to claim 25, which is selected from the group consisting of pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

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