IRAK decomposers 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 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 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 / 123,330, filed December 9, 2020, which is incorporated herein by reference in its entirety.

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

[0003] Background of the invention The ubiquitin-proteasome pathway (UPP) is an important pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to numerous cellular processes and when deficient or imbalanced results in 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, and these are divided into four families: HECT-domain E3, U-box E3, monomeric RING E3 and multisubunit E3. Divided into E3. 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) Title: "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) entitled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) See the title ``Roles of F-box proteins in cancer.''

[0005] UPPs play a major role in the degradation of short-lived regulatory proteins that are important in a variety of fundamental cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. Fulfill. The pathway plays a role in the pathogenesis of several forms of malignancy, several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle wasting. Involved. Many diseases are associated with abnormal UPP, including cell cycle and division, cellular responses to stress and extracellular modulators, morphogenesis of neural networks, cell surface receptors, ion channels, secondary pathways, Adversely affecting DNA repair and the regulation of 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. Namely, (a) diseases resulting from loss of function resulting in stabilization of a particular protein, and (b) diseases resulting from gain of function (i.e., aberrant or accelerated degradation of the protein target).

[0007] UPPs are 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 their recruitment to E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control of protein expression. Such compounds, upon addition to cells or administration to animals or humans, can induce inactivation of proteins of interest and can be useful as biochemical reagents, and can inhibit pathogenic or carcinogenic proteins. (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l): 40-46). There is a continuing need in the art for effective treatment of diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, nonspecific effects and the inability to jointly target and modulate specific classes of proteins (eg, transcription factors) remain obstacles to the development of effective anticancer drugs. Therefore, small molecule therapeutics that target cancer-associated proteins such as interleukin-1 receptor-associated kinase (“IRAK”) by affecting protein degradation mediated by E3 ligases hold promise as therapeutic agents. hold. Therefore, there remains a need to find bifunctional compounds that are IRAK degrading agents that are 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 to solve the problem]

[0009] Summary of the invention This application relates to novel bifunctional compounds that function to recruit IRAK kinase to E3 ubiquitin ligase for degradation, and methods of their preparation and use. In particular, the present disclosure describes its usefulness as a modulator of targeted ubiquitination of IRAK kinases, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. Provides bifunctional compounds with unique properties. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities and are compatible with IRAK kinase degradation / inhibition. Additionally, the present specification provides methods of using an effective amount of a compound described herein for the treatment or amelioration of a disease condition such as cancer, eg, multiple myeloma.

[0010] The present application further relates to bifunctional molecules that are useful for modulating targeted ubiquitination, including bifunctional molecules that couple a cereblon binding moiety to a ligand that binds IRAK kinase. Such compounds have the general formula: [ka] or a pharmaceutically acceptable salt thereof, where each variable is as defined and described herein.

[0011] Compounds of the invention, and pharmaceutically acceptable compositions thereof, have the following general formula I: [ka] It has now been found that by the use of bifunctional molecules with or with pharmaceutically acceptable salts thereof, the IRAK kinase can be targeted for degradation. In general formula I, each variable is as defined and described herein.

[0012] Compounds of the invention, and pharmaceutically acceptable compositions thereof, are useful for treating various diseases, disorders or conditions associated with modulation of signal transduction pathways involving IRAK kinase. Such diseases, disorders, or conditions include those described herein.

[0013] The compounds provided by the present invention are also useful for the study of IRAK enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in body tissues; and the study of kinases, signal transduction pathways, and Useful for comparative evaluation of novel IRAK inhibitors or degraders, or other regulators of cytokine levels. [Form for carrying out the invention]

[0014] Detailed Description of Particular Embodiments 1. General Description of Certain Embodiments of the Invention: Compounds of the 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.

[0015] In certain embodiments, the invention provides formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are independently, covalently bonded, -CR 2 -, -O-, -CF 2 -, [ka] is; or X 1 and X 2 is -CR=CR-; X 3 and X 4 is independently -CH 2 -, -C(O)-, -C(S)-, or [ka] And; Rings X and Y independently have from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogens already illustrated in rings X and Y; a fused ring selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings; R x and R y each independently hydrogen, deuterium, R z , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -C(S)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -Si(OR)R 2 , and -SiR 3 selected from; Each R is independently selected from hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same carbon or nitrogen, optionally together with the atoms between them, in addition to this carbon or nitrogen are independently selected from nitrogen, oxygen, and sulfur forming an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms; Each R z is independently 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, as well as nitrogen, oxygen, and an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched C 1~50 is a hydrocarbon chain, where the 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D) 2 -, -CRF-, -CF 2 -, -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- , [ka] has been replaced by, where: Each -Cy- is independently phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocycrylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl, a 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; an optionally substituted divalent ring selected from 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and IRAK is the IRAK binding moiety.

[0016] 2. Compounds and definitions: Compounds of the invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. 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. Additionally, general principles of organic chemistry are discussed in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and in March's Advanced Organic Chemistry, the entire contents of which are incorporated herein by reference. 5th edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0017] The term "aliphatic" or "aliphatic group" as used herein refers to straight chain (i.e., unbranched) or branched chain, substituted or unsubstituted, fully saturated or or a hydrocarbon chain containing one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic ring that is fully saturated or contains one or more units of unsaturation but is not aromatic. A hydrocarbon (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl") having one point of attachment to the remainder of the molecule. Unless specified otherwise, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 to 3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms. . In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") is fully saturated or contains one or more units of unsaturation, but is not aromatic. monocyclic C, with one point of attachment to the rest of the molecule 3 ~C 6 Refers to hydrocarbons. Suitable aliphatic groups include straight-chain or branched, saturated or unsaturated alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or ( cycloalkyl)alkenyl), but are not limited to these.

[0018] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic ring system (i.e., carbocyclic or heterocyclic) that has at least one bridge. cyclic). As defined by IUPAC, a "bridge" is a multi-atom unbranched chain, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is a Any skeletal atom of the ring system that is bonded to any of the above skeletal atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless specified otherwise, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. An exemplary bridged bicyclic is: [ka] [ka] can be mentioned.

[0019] The term "lower alkyl" means C 1~4 A straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term "lower haloalkyl" means C substituted with one or more halogen atoms. 1~4 A straight or branched alkyl group.

[0021] The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of a basic nitrogen; or a heterocyclic ring) substitutable nitrogen (e.g. N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl), including (as in N-substituted pyrrolidinyl).

[0022] The term "unsaturated" as used herein means a moiety having one or more units of unsaturation.

[0023] As used herein, the term “divalent C 1~8 (or C 1~6 ) means a straight or branched divalent alkylene chain, alkenylene chain, as defined herein; and alkynylene chains.

[0024] The term "alkylene" refers to a divalent alkyl group. "Alkylene chain" refers to a polymethylene group, i.e. -(CH 2 ) n -, where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. 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.

[0025] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0026] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] refers to a divalent cyclopropyl group.

[0027] The term "halogen" means F, Cl, Br, or I.

[0028] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to ring members having a total of 5 to 14 ring members. However, it refers to a monocyclic or bicyclic ring system in which at least one ring within the system is aromatic and each ring within 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 aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, in which one or may have more substituents. As the term "term" is used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl).

[0029] The terms "heteroaryl" and "heteroara-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups of 5 to 10 rings. atoms, preferably 5, 6, or 9 ring atoms; 6, 10, or 14 pi electrons shared in a cyclic configuration; and in addition to the carbon atoms, 1 Refers to a group having ~5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of 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 mean a heteroaromatic ring fused to one or more aryl, alicyclic, or heterocyclic rings. and includes groups in which 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-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenol. Thiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of these terms being optionally substituted. Contains rings. The term "heteroaralkyl" refers to an alkyl group substituted with heteroaryl, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0030] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and include stable 5- to 7-membered a monocyclic, or 7- to 10-membered bicyclic, heterocyclic moiety, either saturated or partially unsaturated, and in addition to carbon atoms, one or more It preferably has 1 to 4 heteroatoms as defined above. When used in reference to ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogens. As an example, in a saturated or partially unsaturated ring with 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, this nitrogen is ) or NH (as in pyrrolidinyl), + It may also be NR (as in N-substituted pyrrolidinyl).

[0031] A heterocyclic ring may be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms may 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, Includes oxazolidinyl, piperazinyl, dioxanyl, dioxolanil, 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, groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolyl) nil). A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted.

[0032] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0033] As described herein, compounds of the invention may include "optionally substituted" moieties. Generally, the term "substituted" means that one or more hydrogens on the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have suitable substituents on each substitutable portion of the group, and at more than one position in any given structure. When can be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically possible compounds. The term "stable" as used herein refers to the production, detection, and, in certain embodiments, of one or more of the purposes disclosed herein. Refers to compounds that remain substantially unchanged when subjected to conditions that permit their recovery, purification, and use for purposes.

[0034] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group include, independently, halogen;-(CH 2 ) 0~4 R ○ ;-(CH 2 ) 0~4 OR ○ ;-O(CH 2 ) 0~4 R ○ , -O-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 CH(OR ○ ) 2 ;-(CH 2 ) 0~4 S.R. ○ ;-(CH 2 ) 0~4 Ph(This is R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph(This is R ○ );-CH=CHPh (which can be substituted with R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 -pyridyl (this is R ○ );-NO 2 ;-CN;-N 3 ;-(CH 2 ) 0~4 N(R ○ ) 2 ;-(CH 2 ) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH 2 ) 0~4 N(R ○ )C(O)NR ○ 2 ;-N(R ○ )C(S)NR ○ 2 ;-(CH 2 ) 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 ○ ;-(CH 2 ) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 C(O)SR ○ ;-(CH 2 ) 0~4 C(O)OSiR ○ 3 ;-(CH 2 ) 0~4 OC(O)R ○ ;-OC(O)(CH 2 ) 0~4 SR-;SC(S)SR ○ ;-(CH 2 ) 0~4 SC(O)R ○ ;-(CH 2 ) 0~4 C(O)NR ○ 2 ;-C(S)NR ○ 2 ;-C(S)SR ○ ;-SC(S)SR ○ ,-(CH 2 ) 0~4 OC(O)NR ○ 2 ;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH 2 C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH 2 ) 0~4 SSR ○ ;-(CH 2 ) 0~4 S(O) 2 R ○ ;-(CH 2 ) 0~4 S(O) 2 OR ○ ;-(CH 2 ) 0~4 OS(O) 2 R ○ ;-S(O) 2 NR ○ 2 ;-(CH 2 ) 0~4 S(O)R ○ ;-N(R ○ )S(O) 2 NR ○ 2 ;-N(R ○ )S(O) 2 R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2 ;-P(O) 2 R ○ ;-P(O)R ○ 2 ;-OP(O)R ○ 2 ;-OP(O)(OR ○ ) 2 ;SiR ○ 3 ;-(C 1~4 linear or branched alkylene)O-N(R ○ ) 2 ; or -(C 1~4 linear or branched alkylene)C(O)O-N(R ○ ) 2, where each R ○ may be substituted as defined below and independently hydrogen, C 1~6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2 -(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated or partially unsaturated ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur , or an aryl ring, or notwithstanding the above definition, R ○ two independent occurrences of, together with the atom(s) between them, have from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3 It forms a saturated, partially unsaturated, or aryl monocyclic or bicyclic ring of 1 to 12 members, which may be substituted as defined below.

[0035] R ○ (R ○ Suitable monovalent substituents on a ring (formed by two independent occurrences of 2 ) 0~2 R ● ,-(Halo R ● ), -(CH 2 ) 0~2 OH, -(CH 2 ) 0~2 OR ● ,-(CH 2 ) 0~2 CH(OR ● ) 2 ;-O(Halo R ● ), -CN, -N 3 ,-(CH 2 ) 0~2 C(O)R ● ,-(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● ,-(CH 2 ) 0~2 S.R. ● ,-(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 N.H. 2 ,-(CH 2 ) 0~2 NHR ● ,-(CH 2 ) 0~2 NR ● 2 ,-NO 2 ,-SiR ● 3 ,-OSiR ● 3 , -C(O)SR ● , -(C 1~4 linear or branched alkylene)C(O)OR ● , or -SSR ● , where each R ● is unsubstituted or substituted only with one or more halogens if preceded by "halo", and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R ○ Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0036] Suitable divalent substituents on saturated carbon atoms of "optionally substituted" groups include: =O, =S, =NNR * 2 ,=NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O) 2 R * ,=NR * ,=NOR * , -O(C(R * 2 )) 2~3 O-, or -S(C(R * 2 )) 2~3 S-. Here R * Each independent occurrence of hydrogen, C may be substituted as defined below 1~6 selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ru. Suitable divalent substituents attached to the vicinal substitutable carbons of the "optionally substituted" group include -O(CR * 2 ) 2~3 O- is mentioned, where R * Each independent occurrence of hydrogen, C may be substituted as defined below 1~6 selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ru.

[0037] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 ,-NHR ● ,-NR ● 2 , or -NO 2 is listed, where each R ● is unsubstituted or substituted only with one or more halogens if preceded by "halo", and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0038] Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include -R † ,-NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R † are listed; where each R † is independently hydrogen, C which may be substituted as defined below 1~6 Aliphatic, unsubstituted -OPh, or unsubstituted 5- to 6-membered saturated, partially unsaturated ring, or aryl having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. ring or, notwithstanding the above definition, R † two independent occurrences of, together with the atom(s) between them, have from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an unsubstituted forms a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring.

[0039] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 ,-NHR ● ,-NR ● 2 , or -NO 2 , where each R ● is unsubstituted or substituted only with one or more halogens if preceded by "halo", and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0041] As used herein, the term "pharmaceutically acceptable salts" means that, within the scope of sound medical judgment, Refers to salts that are suitable for use in contact with animal tissue and that are proportionate to 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 this 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 inorganic acids (e.g. hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g. acetic, oxalic, maleic). , tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate. , camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate salt, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonic acid Salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate , phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. .

[0042] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 alkyl) 4 Salt is an example. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Additional pharmaceutically acceptable salts include, where appropriate, salts such as halide, hydroxide, carbonate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate ions. Contains non-toxic ammonium, quaternary ammonium, and amine cations formed using ions.

[0043] Unless otherwise stated, structures depicted herein also refer to all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., at each asymmetric center. is meant to include R and S configurations, double bond isomers of Z and E, and conformational isomers of Z and E. Therefore, 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. Additionally, 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 where hydrogen is replaced by deuterium or tritium, or where carbon is 13 C or 14 Compounds having the invention in which C is replaced with 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.

[0044] As used herein, the term "inhibitor" is defined as a compound that binds with measurable affinity and / or inhibits IRAK kinase. In certain embodiments, the 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.

[0045] As used herein, the term "degrading agent" refers to the ability to bind with measurable affinity and / or inhibit both IRAK kinase and E3 ligase, resulting in the ubiquitination and subsequent It is defined as a heterobifunctional compound that results in decomposition. In certain embodiments, the degrading agent has 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 DC 50 has.

[0046] A compound of the 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 the detectable moiety may be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached 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 may be attached directly to the provided compound or via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached by click chemistry. In some embodiments, such moieties may be attached by 1,3-cycloaddition of the azide with the alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and have been described by Rostovtsev et al., Angew.Chem.Int.Ed.2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57. The following are listed.

[0047] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and relates to any moiety that can be detected, including primary and secondary labels. Radioactive isotopes (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.

[0048] 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 for the generation of a detectable signal. For biotin, a streptavidin-enzyme conjugate may be included as a secondary intermediate. For antigen labels, secondary intermediates can include antibody-enzyme conjugates. 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 produces a signal that is detected.

[0049] As used herein, the terms "fluorescent label," "fluorochrome," 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 Fluor350, Alexa Fluor488, Alexa Fluor532, Alexa Fluor546, Alexa Fluor568, Alexa Fluor594, Alexa Fluor633, Alexa Fluor660 and Alexa Fluor680), 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 dye (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-dichloro-2',7' -Dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, 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, Rhodoll Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl -Rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X, but are not limited to these.

[0050] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6- Electrophore releasing tags such as tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives are included. The synthesis and utility of these mass tags is described in U.S. Patent Nos. 4,650,750; 4,709,016; 5,360,8191; There is. 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. Not done. 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.

[0051] The terms "measurable affinity" and "measurably inhibit", as used herein, refer to a compound of the invention or a composition thereof and a sample containing IRAK protein kinase, and the compound also Means a measurable change in IRAK protein kinase activity between an equivalent sample containing IRAK protein kinase in the absence of that composition.

[0052] 3. Description of exemplary embodiments: The compounds of the present application have the following general structure that couples the cereblon binding moiety to a ligand that binds to IRAK kinase: [ka] or a pharmaceutically acceptable salt thereof, wherein: IRAK is an IRAK-binding moiety capable of binding to one or more of IRAK1, IRAK2, IRAK3, or IRAK4; L is a divalent moiety that binds IRAK to LBM; and LBM is the ligase binding moiety. Ligase binding moiety (LBM)

[0053] As noted above, in certain embodiments, the present invention provides the formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in the embodiments herein: X 1 and X 2 are independently, covalently bonded, -CR 2 -, -O-, -CF 2 -, [ka] is; or X 1 and X 2 is -CR=CR-; X 3 and X 4 is independently -CH 2 -, -C(O)-, -C(S)-, or [ka] And; Rings X and Y independently have from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogens already illustrated in rings X and Y; a fused ring selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings; R x and R y each independently hydrogen, deuterium, R z , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -C(S)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -Si(OR)R 2 , and -SiR 3 selected from; Each R is independently selected from hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same carbon or nitrogen, optionally together with the atoms between them, in addition to this carbon or nitrogen are independently selected from nitrogen, oxygen, and sulfur forming an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms; Each R z is independently 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, as well as nitrogen, oxygen, and an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2, 3 or 4.

[0054] X as defined above and described herein 1 and X 2 are independently, covalently bonded, -CR 2 -, -O-, -CF 2 -, [ka] or X 1 and X 2 is -CR=CR-.

[0055] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is-CR 2 -is. In some embodiments, X 1 -CH 2 -is. In some embodiments, X 1 is -O-. In some embodiments, X 1 -CF 2 -is. In some embodiments, X 1 teeth [ka] It is. In some embodiments, X 2 is a covalent bond. In some embodiments, X 2 is-CR 2 -is. In some embodiments, X 2 -CH 2 -is. In some embodiments, X 2 is -O-. In some embodiments, X 2 -CF 2 -is. In some embodiments, X 2 teeth [ka] It is. In some embodiments, X 1 and X 2 is -CR=CR-. In some embodiments, X 1 and X 2 is -CH=CH-.

[0056] In some embodiments, X 1 and X 2 are independently selected from those shown in Table 1 Compounds.

[0057] X as defined above and described herein 3 and X 4 is independently -CH 2 -, -C(O)-, -C(S)-, or [ka] It is.

[0058] In some embodiments, X 3 -CH 2 -is. In some embodiments, X 3 is -C(O)-. In some embodiments, X 3 is -C(S)-. In some embodiments, X 3 teeth [ka] It is. In some embodiments, X 4 -CH 2 -is. In some embodiments, X 4 is -C(O)-. In some embodiments, X 4 is -C(S)-. In some embodiments, X 4 teeth [ka] It is.

[0059] In some embodiments, X 3 and X 4 is selected from those shown in Table 1 Compounds.

[0060] As defined above and described herein, Ring X and Ring Y independently include nitrogen, oxygen, and sulfur in addition to the nitrogens already illustrated in Ring X and Ring Y. A fused ring selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings having 0 to 4 heteroatoms selected as follows.

[0061] In some embodiments, Ring X and Ring Y are independently selected from 0 to 4 nitrogens, in addition to the nitrogens already depicted in Ring It is a fused ring selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings having 5 to 6 heteroatoms.

[0062] In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is. In some embodiments, ring X is [ka] It is.

[0063] In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is. In some embodiments, ring Y is [ka] It is.

[0064] In certain embodiments, ring X and ring Y are selected from those shown in the compounds of Table 1.

[0065] As defined above and described herein, R x and R y each independently hydrogen, deuterium, R z , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CFR 2 ,-CF 2 R, -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -C(S)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -Si(OR)R 2 , and -SiR 3 selected from.

[0066] In some embodiments, R x is hydrogen. In some embodiments, R x is Deuterium. In some embodiments, R x is R z It is. In some embodiments, R x is a halogen. In some embodiments, R x is -CN. In some embodiments, R x Ha-NO 2 It is. In some embodiments, R x is -OR. In some embodiments, R x is -SR. In some embodiments, R x -NR 2 It is. In some embodiments, R x is-S(O) 2 It is R. In some embodiments, R x is-S(O) 2 NR 2 It is. In some embodiments, R x is -S(O)R. In some embodiments, R x -CFR 2 It is. In some embodiments, R x -CF 2 It is R. In some embodiments, R x -CF 3 It is. In some embodiments, R x is-CR 2 (OR). In some embodiments, R x is-CR 2 (NR 2 ). In some embodiments, R x is -C(O)R. In some embodiments, R x is -C(O)OR. In some embodiments, R x -C(O)NR 2 It is. In some embodiments, R x is -C(O)N(R)OR. In some embodiments, R x is -OC(O)R. In some embodiments, R x -OC(O)NR 2 It is. In some embodiments, R x -C(S)NR 2 It is. In some embodiments, R x is -N(R)C(O)OR. In some embodiments, R x is -N(R)C(O)R. In some embodiments, R x -N(R)C(O)NR2 It is. In some embodiments, R x is-N(R)S(O) 2 It is R. In some embodiments, R x is-OP(O)R 2 It is. In some embodiments, R x is-OP(O)(OR) 2 It is. In some embodiments, R x is-OP(O)(OR)NR 2 It is. In some embodiments, R x is-OP(O)(NR 2 ) 2 It is. In some embodiments, R x -Si(OR)R 2 It is. In some embodiments, R x -SiR 3 It is.

[0067] In some embodiments, R y is hydrogen. In some embodiments, R y is Deuterium. In some embodiments, R y is R z It is. In some embodiments, R y is a halogen. In some embodiments, R y is -CN. In some embodiments, R y Ha-NO 2 It is. In some embodiments, R y is -OR. In some embodiments, R y is -SR. In some embodiments, R y -NR 2 It is. In some embodiments, R y is-S(O) 2 It is R. In some embodiments, R y is-S(O) 2 NR 2 It is. In some embodiments, R y is -S(O)R. In some embodiments, R y -CFR 2 It is. In some embodiments, R y -CF 2 It is R. In some embodiments, R y -CF 3 It is. In some embodiments, R y is-CR 2 (OR). In some embodiments, R y is-CR 2 (NR 2 ). In some embodiments, R y is -C(O)R. In some embodiments, R y is -C(O)OR. In some embodiments, R y -C(O)NR 2 It is. In some embodiments, R y is -C(O)N(R)OR. In some embodiments, R y is -OC(O)R. In some embodiments, R y -OC(O)NR 2 It is. In some embodiments, R y -C(S)NR 2 It is. In some embodiments, R y is -N(R)C(O)OR. In some embodiments, R y is -N(R)C(O)R. In some embodiments, R y -N(R)C(O)NR 2 It is. In some embodiments, R y is-N(R)S(O) 2 It is R. In some embodiments, R y is-OP(O)R 2 It is. In some embodiments, R y is-OP(O)(OR) 2 It is. In some embodiments, R y is-OP(O)(OR)NR 2 It is. In some embodiments, R y is-OP(O)(NR 2 ) 2 It is. In some embodiments, R y -Si(OR)R 2 It is. In some embodiments, R y -SiR 3 It is.

[0068] In certain embodiments, R x and R y each of which is selected from those shown in Table 1 Compounds.

[0069] As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or two R groups on the same carbon or nitrogen between them an optionally substituted carbon or nitrogen, optionally taken together with the atoms in form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0070] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1~6 It is aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or moiety having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is an unsaturated heterocyclic. 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. be. In some embodiments, two R groups on the same carbon or nitrogen, optionally together with atoms between them, include nitrogen, oxygen, and sulfur in addition to this carbon or nitrogen. form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from

[0071] In certain embodiments, R is selected from those shown in the compounds of Table 1.

[0072] As defined above and described herein, each R z is independently 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, as well as nitrogen, oxygen, and an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur.

[0073] In some embodiments, R z is C with substitutions as necessary 1~6 It is aliphatic. In some embodiments, R z is optionally substituted phenyl. In some embodiments, R z 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. be. 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.

[0074] In certain embodiments, R z is selected from those shown in Table 1 Compounds.

[0075] As defined above and described herein, x is 0, 1, 2, 3 or 4.

[0076] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0077] In certain embodiments, x is selected from those shown in the compounds of Table 1.

[0078] As defined above and described herein, y is 0, 1, 2, 3 or 4.

[0079] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4.

[0080] In certain embodiments, y is selected from those shown in the compounds of Table 1.

[0081] In some embodiments, the invention provides X 1 and X 2 ga-CH 2 - and X 3 and X 4 is -C(O)-, and the formula I-a-1: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, ring X, ring Y, R x ,R y , x, and y, both alone and in combination, are as defined above and described in the embodiments herein.

[0082] In some embodiments, the invention provides X 1 and X 2 ga-CH 2 - and X 3 and X 4 is -C(O)-, and the ring Y is [ka] and formula I-a-2: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, ring X, R x ,R y , x, and y, both alone and in combination, are as defined above and described in the embodiments herein.

[0083] In some embodiments, the invention provides X 1 and X 2 ga-CH 2 - and X 3 and X 4 is -C(O)-, and ring X is [ka] and formula I-a-3: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, ring Y, R x ,R y , x, and y, both alone and in combination, are as defined above and described in the embodiments herein.

[0084] In some embodiments, the invention provides X 1 and X 2 ga-CH 2 - and X 3 and X 4 is -C(O)-, and ring X is [ka] , and the ring Y is [ka] and formula I-a-4: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, R x ,R y , x, and y, both alone and in combination, are as defined above and described in the embodiments herein.

[0085] In some embodiments, the LBM is [ka] It is. In some embodiments, the LBM is [ka] It is. IRAK binding part (IRAK)

[0086] As defined above and described herein, IRAK is an IRAK binding moiety capable of binding to one or more of IRAK1, IRAK2, IRAK3, or IRAK4. In some embodiments, IRAK is an IRAK 4 binding moiety.

[0087] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety, whereby formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is a 4- to 10-membered saturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a formula ring; Ring B is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or 1 to 3 members independently selected from nitrogen, oxygen, and sulfur. a 5- to 9-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is an aryl ring; Ring C is phenyl or a 5- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 and L 3 Each of is independently a covalent bond, or a C 1~3 a divalent straight or branched saturated or unsaturated hydrocarbon chain in which one to three methylene units of the chain are independently -O-, -C(O)- , -C(S)-, -C(R) 2 -, -CH(R)-, -CF(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 -or -CR=CR- is replaced as appropriate; Each R 1 are independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)(NR)R, -P(O)(OR) 2 , -P(O)(NR 2 ) 2 ,-CFR 2 ,-CF 2 (R), -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, or -C(O)NR 2 And; Each R is independently hydrogen, deuterium, or an optionally substituted group, where the optionally substituted group is 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same atom, optionally together with the atoms between them, in addition to the atom to which they are attached, are independently selected from nitrogen, oxygen, and sulfur. optionally substituted 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, forming a bridged bicyclic, spiro, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)(NR)R, -P(O)(OR) 2 , -P(O)(NR 2 ) 2 ,-CFR 2 ,-CF 2 (R), -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 R; R 4 teeth, [ka] , hydrogen, or an optionally substituted group, where the optionally substituted group is selected from C 1~6 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic, aliphatic or having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from monocyclic, bicyclic, bridged bicyclic, or spiro rings; Ring D is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or 1 to 3 members independently selected from nitrogen, oxygen, and sulfur. a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3 are independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)(NR)R, -P(O)(OR) 2 , -P(O)(NR 2 ) 2 ,-CFR 2 ,-CF 2 (R), -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 R; Each R 5 is independently C 1~6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated, carbocyclic, or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur ring, and an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. ; each n is 0, 1, or 2; each m is 0, 1, 2, 3 or 4; and Each p is 0, 1, 2, 3 or 4.

[0088] As generally defined above, Ring A is a 4- to 10-membered saturated monocyclic or bicyclic ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a carbocyclic or heterocyclic ring.

[0089] In some embodiments, Ring A is cyclohexyl.

[0090] In some embodiments, Ring A is selected from those illustrated in Table 1 below.

[0091] As generally defined above, Ring B is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic ring, or independent of nitrogen, oxygen, and sulfur. or a 5- to 9-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a monocyclic or bicyclic heteroaryl ring.

[0092] 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 independently selected from nitrogen, oxygen, and sulfur. It is a heterocyclic ring having 1 to 3 heteroatoms. In some embodiments, Ring B is a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is.

[0093] In some embodiments, Ring B is [ka] It is. In some embodiments, Ring B is [ka] It is. In some embodiments, Ring B is [ka] It is. In some embodiments, Ring B is [ka] It is.

[0094] As generally defined above, ring C is phenyl, or a 5- to 10-membered monocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a bicyclic heteroaryl ring.

[0095] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 5- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is.

[0096] In some embodiments, ring C is [ka] It is. In some embodiments, ring C is [ka] It is.

[0097] In some embodiments, Ring C is selected from those illustrated in Table 1 below.

[0098] As generally defined above, L 2 is a covalent bond, or C 1~3 a divalent moiety selected from a divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to three methylene units of the chain are independently -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -CF(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or -CR=CR- as appropriate.

[0099] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is C 1~3 a divalent straight or branched saturated or unsaturated hydrocarbon chain in which the 1 to 3 methylene units of the chain are independently -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -CF(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or -CR=CR- as appropriate. In some embodiments, L 2 is C 1~3 It is aliphatic. In some embodiments, L 2 -CH 2 -is. In some embodiments, L 2 is -C(D)(H)-. In some embodiments, L 2 is-C(D) 2 -is. In some embodiments, L 2 -CH 2 CH 2 -is. In some embodiments, L 2 is -NR-. In some embodiments, L 2 -CH 2 It is NR-. In some embodiments, L 2 is or -O-. In some embodiments, L 2 -CH 2 It is O-. In some embodiments, L 2 is -S-. In some embodiments, L 2 is -OC(O)-. In some embodiments, L 2 is -C(O)O-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is -S(O)-. In some embodiments, L 2 is-S(O) 2 -is. In some embodiments, L 2 -NRS(O) 2 -is. In some embodiments, L 2 is-S(O) 2 It is NR-. In some embodiments, L 2 is -NRC(O)-. In some embodiments, L 2 is -C(O)NR-. In some embodiments, L 2 is -OC(O)NR-. In some embodiments, L 2 is -NRC(O)O-.

[0100] As generally defined above, L 3 is a covalent bond, or C 1~3a divalent moiety selected from a divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to three methylene units of the chain are independently -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -CF(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or -CR=CR- as appropriate.

[0101] In some embodiments, L 3 is C 1~3 a divalent straight or branched saturated or unsaturated hydrocarbon chain in which the 1 to 3 methylene units of the chain are independently -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -CF(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or -CR=CR- as appropriate. In some embodiments, L 3 is C 1~3 It is aliphatic. In some embodiments, L 3 -CH 2 -is. In some embodiments, L 3 is -C(D)(H)-. In some embodiments, L 3 is-C(D) 2 -is. In some embodiments, L 3 -CH 2 CH 2 -is. In some embodiments, L 3 is -NR-. In some embodiments, L 3 -CH 2 It is NR-. In some embodiments, L 3 is or -O-. In some embodiments, L 3 -CH 2 It is O-. In some embodiments, L 3 is -S-. In some embodiments, L 3 is -OC(O)-. In some embodiments, L 3 is -C(O)O-. In some embodiments, L 3 is -C(O)-. In some embodiments, L 3 is -S(O)-. In some embodiments, L 3 is-S(O) 2 -is. In some embodiments, L 3 -NRS(O) 2 -is. In some embodiments, L 3 is-S(O) 2 It is NR-. In some embodiments, L 3 is -NRC(O)-. In some embodiments, L 3 is -C(O)NR-. In some embodiments, L 3 is -OC(O)NR-. In some embodiments, L 3 is -NRC(O)O-.

[0102] In some embodiments, L 2 and L 3 is selected from those illustrated in Table 1 below.

[0103] As generally defined above, each R 1 are independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)(NR)R, -P(O)(OR) 2 , -P(O)(NR 2 ) 2 ,-CF 2 (R), -CFR 2 ,-CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -N + (O - )R 2 ,-OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -P(O)R 2 ,-SiR 3 , -Si(OR)R 2 ,-SCIENCE FICTION 5 ,or [ka] It is.

[0104] In some embodiments, each R 1 are independently hydrogen. In some embodiments, R 1 is Deuterium. In some embodiments, each R 1 is independently -R 5 It is. In some embodiments, each R 1 are independently halogens. In some embodiments, each R 1 is independently -CN. In some embodiments, each R 1 is independently -NO 2 It is. In some embodiments, each R 1 is independently -OR. In some embodiments, each R 1 is independently -SR. In some embodiments, each R 1 is independently -NR 2 It is. In some embodiments, each R 1 are independently -S(O) 2 It is R. In some embodiments, each R 1 are independently -S(O) 2 NR 2 It is. In some embodiments, each R 1 are independently -S(O)R. In some embodiments, each R 1 are independently -S(O)(NR)R. In some embodiments, each R 1 are independently -P(O)(OR) 2 It is. In some embodiments, each R 1 are independently -P(O)(NR 2 ) 2 It is. In some embodiments, each R 1 is independently -CF 2 (R). In some embodiments, each R 1 is independently -CFR 2 It is. In some embodiments, each R 1 is independently -CF 3 It is. In some embodiments, each R 1 is independently -CR 2 (OR). In some embodiments, each R 1 is independently -CR 2 (NR 2 ). In some embodiments, each R 1 are independently -C(O)R. In some embodiments, each R 1 are independently -C(O)OR. In some embodiments, each R 1 are independently -C(O)NR 2 It is. In some embodiments, each R 1 are independently -C(O)N(R)OR. In some embodiments, each R 1 are independently -OC(O)R. In some embodiments, each R 1 are independently -OC(O)NR 2 It is. In some embodiments, each R 1 are independently -N(R)C(O)OR. In some embodiments, each R 1 are independently -N(R)C(O)R. In some embodiments, each R 1 are independently -N(R)C(O)NR 2 It is. In some embodiments, each R 1 are independently -N(R)S(O) 2 It is R. In some embodiments, each R 1 is independently -N + (O - )R 2 It is. In some embodiments, each R 1 is independently -OP(O)R 2 It is. In some embodiments, each R 1 is independently -OP(O)(OR) 2 It is. In some embodiments, each R 1 are independently -OP(O)(OR)NR 2 It is. In some embodiments, each R 1 is independently -OP(O)(NR 2 ) 2 It is. In some embodiments, each R 1 are independently -P(O)R 2 It is. In some embodiments, each R 1 is independently -SiR 3 It is. In some embodiments, each R1 is independently -Si(OR)R 2 It is. In some embodiments, each R 1 is independently -SF 5 It is. In some embodiments, each R 1 is independently, [ka] It is.

[0105] In some embodiments, R 1 -CHF 2 It is. In some embodiments, R 1 is -C(OH)(CH 3 ) 2 It is. In some embodiments, R 1 is -OMe.

[0106] As generally defined above, R 2 and R 3 each independently hydrogen, deuterium, -R 5 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)(NR)R, -P(O)(OR) 2 , -P(O)(NR 2 ) 2 ,-CFR 2 ,-CF 2 (R), -CF 3 ,-CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -N + (O - )R 2 ,-OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -P(O)R 2 ,-SiR 3 , -Si(OR)R 2 ,-SCIENCE FICTION 5 ,or [ka] It is.

[0107] In some embodiments, R 2 and R 3 Each of is independently hydrogen. In some embodiments, R 2 and R 3 Each of the is independently a deuterium. In some embodiments, R 2 and R 3 Each of the -R 5 It is. In some embodiments, R 2 and R 3 Each of is independently a halogen. In some embodiments, R 2 and R 3 Each of is independently -CN. In some embodiments, R 2 and R 3 Each of them is independently -NO 2 It is. In some embodiments, R 2 and R 3 Each of is independently -OR. In some embodiments, R 2 and R 3 Each of them is independently -SR. In some embodiments, R 2 and R 3 Each of them is independently -NR 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -S(O) 2 It is R. In some embodiments, R 2 and R 3 Each of them is independently -S(O) 2 NR 2 It is. In some embodiments, R 2 and R 3 Each of is independently -S(O)R. In some embodiments, R 2 and R 3 Each of is independently -S(O)(NR)R. In some embodiments, R 2 and R 3 Each of them is independently -P(O)(OR) 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -P(O)(NR 2 ) 2 It is. In some embodiments, R 2 and R 3 Each of the -CFR independently 2 It is. In some embodiments, R 2 and R 3 Each of the -CF 2 (R). In some embodiments, R 2 and R 3 Each of the -CF 3 It is. In some embodiments, R 2 and R 3 Each of them is independently -CR 2 (OR). In some embodiments, R 2 and R 3 Each of them is independently -CR 2 (NR 2 ). In some embodiments, R 2 and R 3 Each of is independently -C(O)R. In some embodiments, R 2 and R 3 Each of is independently -C(O)OR. In some embodiments, R 2 and R 3 Each of is independently -C(O)NR 2 It is. In some embodiments, R 2 and R 3 Each of is independently -C(O)N(R)OR. In some embodiments, R 2 and R 3 Each of is independently -OC(O)R. In some embodiments, R 2 and R 3 Each of them is independently -OC(O)NR 2 It is. In some embodiments, R 2 and R 3 Each of is independently -N(R)C(O)OR. In some embodiments, R 2 and R 3 Each of is independently -N(R)C(O)R. In some embodiments, R 2 and R 3 Each of them is independently -N(R)C(O)NR 2 It is. In some embodiments, R 1 and R 2 Each of them is independently -N(R)S(O) 2 It is R. In some embodiments, R 2 and R 3 Each of the -N + (O - )R 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)R 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)(OR) 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)(OR)NR 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)(NR 2 ) 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -P(O)R 2 It is. In some embodiments, R 2 and R 3 Each of the -SiR 3 It is. In some embodiments, R 2 and R 3 Each of is independently -Si(OR)R 2 It is. In some embodiments, R 2 and R 3 Each of them is independently -SF 5 It is. In some embodiments, R 2 and R 3 each independently, [ka] It is.

[0108] In some embodiments, R 2 is fluoro. In some embodiments, R 2 is Chloro. In some embodiments, R 2 -CF3 It is. In some embodiments, R 4 teeth, [ka] It is. In some embodiments, R 4 teeth, [ka] It is.

[0109]

[0110] In some embodiments, R 1 ,R 2 , and R 3 each independently selected from those illustrated in Table 1 below.

[0111] As generally defined above, R 4 teeth, [ka] , hydrogen, or an optionally substituted group, where the optionally substituted group is selected from C 1~6 aliphatic or 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from cyclic, bicyclic, or spiro rings.

[0112] In some embodiments, R 4 teeth [ka] It is. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1~6 An optionally substituted group selected from aliphatic groups. In some embodiments, R 4 is an optionally substituted 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Cyclic, monocyclic, bicyclic, bridged bicyclic, or spiro ring.

[0113] In some embodiments, R 4 teeth, [ka] It is. In some embodiments, R 4 teeth, [ka] It is.

[0114] As generally defined above, Ring D is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic ring, or independent of nitrogen, oxygen, and sulfur. or a 5- to 6-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a heteroaryl ring.

[0115] In some embodiments, Ring D is phenyl. In some embodiments, ring D is a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or independently selected from nitrogen, oxygen, and sulfur. It is a heterocyclic ring having 1 to 3 heteroatoms. In some embodiments, Ring D is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some embodiments, Ring D is selected from those illustrated in Table 1 below.

[0117] As generally defined above, each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same atom are selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from and optionally substituted together, having, in addition to the atoms to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It forms a 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring.

[0118] In some embodiments, each R is independently hydrogen. In some embodiments, each R is C 1~6 An optionally substituted group selected from aliphatic groups. In some embodiments, each R is optionally substituted phenyl. In some embodiments, each R is an optionally substituted 4- to 7-membered saturated or moiety having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is unsaturated heterocyclic. In some embodiments, each R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is. In some embodiments, two R groups on the same atom, optionally together with the atoms between them, contain, in addition to the atoms to which they are attached, nitrogen, oxygen, and optionally substituted 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic ring having 0 to 3 heteroatoms independently selected from sulfur form a bridged bicyclic, spiro, or heteroaryl ring.

[0119] In some embodiments, each R is selected from those illustrated in Table 1 below.

[0120] As generally defined above, each R 5 is independently C 1~6 a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; It is an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, each R 5 is independently C 1~6 An optionally substituted group selected from aliphatic groups. In some embodiments, each R 5 are independently optionally substituted phenyl. In some embodiments, each R 5 is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a heterocyclic ring. In some embodiments, each R 5 is independently an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0122] In some embodiments, each R 5 is selected from those illustrated in Table 1 below.

[0123] As generally defined above, each n is independently 0, 1, or 2.

[0124] In some embodiments, each n is independently 0. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2.

[0125] As generally defined above, each of m and p is independently 0, 1, 2, 3 or 4.

[0126] In some embodiments, each of m and p is independently 0. In some embodiments, each of m and p is independently 1. In some embodiments, each of m and p is independently 2. In some embodiments, each of m and p is independently 3. In some embodiments, each of m and p is independently 4.

[0127] In some embodiments, each of m and p is selected from those illustrated in Table 1 below.

[0128] In some embodiments, the invention provides that IRAK is of formula I-aa, as shown, and formula I-aa-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring B, ring C, R 1 ,R 2 ,R 4, n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0129] In some embodiments, the invention provides that IRAK is of formula I-aa, as shown, and formula I-aa-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 2 ,L 3 , ring A, ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0130] In some embodiments, the invention provides that IRAK is of formula I-aa, as shown, and formula I-aa-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0131] In some embodiments, the invention provides that IRAK is of formula I-aa, as shown, and formula I-aa-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 2 ,L 3 , ring A, ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0132] In some embodiments, the invention provides that IRAK is of formula I-aa, in formula I-aa, ring A is cyclohexylenyl, and L 2 is a covalent bond and has the formula I-aa-5: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 3 , ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0133] In some embodiments, the invention provides that IRAK is of formula I-aa, in formula I-aa, ring A is cyclohexylenyl, and L 2 is a covalent bond and has the formula I-aa-6: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 3 , ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0134] In some embodiments, the invention provides that IRAK is of formula I-aa, in formula I-aa, ring A is cyclohexylenyl, and L 2 is a covalent bond and has the formula I-aa-7: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0135] In some embodiments, the invention provides that IRAK is of formula I-aa, in formula I-aa, ring A is cyclohexylenyl, and L 2 is the coolant bond and has the formula I-aa-8: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 3 , ring B, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0136] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is indazolyl, having the formula I-aa-9: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0137] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is the coolant bond, and Ring B is indazolyl and has the formula I-aa-10: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0138] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is indazolyl, having the formula I-aa-11: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0139] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is the coolant bond, and Ring B is indazolyl and has the formula I-aa-12: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0140] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is 6-azindazolyl, having the formula I-aa-13: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0141] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a coolant bond, and ring B is 6-azindazolyl, with formula I-aa-14: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0142] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is 6-azindazolyl, having the formula I-aa-15: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0143] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a coolant bond, and ring B is 6-azindazolyl, with formula I-aa-16: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0144] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-17: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0145] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-18: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0146] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-19: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0147] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-20: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0148] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is pyrazolyl, having the formula I-aa-21: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0149] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is pyrazolyl, and has the formula I-aa-22: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0150] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is pyrazolyl, having the formula I-aa-23: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0151] In some embodiments, the invention provides that IRAK is of formula I-aa, and in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is pyrazolyl, having the formula I-aa-24: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0152] In some embodiments, the invention provides a method in which x is 1 and R x is methyl and IRAK is of formula I-aa, in which ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-25: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, ring Y, R y ,y,L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0153] In some embodiments, the invention provides a method in which x is 1 and R x is methyl and IRAK is of formula I-aa, in which ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-26: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring X, R y ,y,L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0154] In some embodiments, the invention provides a method in which x is 1 and R x is methyl and IRAK is of formula I-aa, in which ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-27: [ka] or a pharmaceutically acceptable salt thereof, wherein L, ring Y, R y ,y,L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0155] In some embodiments, the invention provides a method in which x is 1 and R x is methyl and IRAK is of formula I-aa, in which ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-28: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R y ,y,L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0156] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-29: [ka] or a pharmaceutically acceptable salt thereof, wherein ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0157] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-30: [ka] or a pharmaceutically acceptable salt thereof, wherein ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0158] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is benzothiazolyl, having the formula I-aa-31: [ka] or a pharmaceutically acceptable salt thereof, wherein rings Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0159] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2is a covalent bond, and ring B is benzothiazolyl, and has the formula I-aa-32: [ka] or a pharmaceutically acceptable salt thereof, wherein R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0160] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and Ring B is indazolyl, having the formula I-aa-33: [ka] or a pharmaceutically acceptable salt thereof, wherein ring X, ring Y, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0161] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is indazolyl, having the formula I-aa-34: [ka] or a pharmaceutically acceptable salt thereof, wherein ring X, R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0162] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and ring B is indazolyl, having the formula I-aa-35: [ka] or a pharmaceutically acceptable salt thereof, wherein rings Y, R x ,R y , x, y, L 2 ,L 3 , ring A, ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0163] In some embodiments, the invention provides that L is [ka] and IRAK is formula I-aa, in formula I-aa, ring A is cyclohexylenyl and L 2 is a covalent bond, and Ring B is indazolyl, having the formula I-aa-36: [ka] or a pharmaceutically acceptable salt thereof, wherein R x ,R y , x, y, L 3 , ring C, R 1 ,R 2 ,R 4 , n, and m, both alone and in combination, are as defined above and described in the embodiments herein.

[0164] In certain embodiments, the invention provides that IRAK is an IRAK-4 inhibitor [ka] [ka] , thereby giving the formula I-dd-1 or I-dd-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: A is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted (Cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl-NR x -, optionally substituted heterocycloalkyl-NR x -, optionally substituted aryl-NR x -, optionally substituted heteroaryl-NR x -, optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted aryl-O- or optionally substituted heteroaryl -O-; for example, where each optional substituent is independently R z represents the existence of; B is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, -NR a R b , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (cyclo alkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl-NR x -, optionally substituted heterocycloalkyl-NR x -, optionally substituted aryl-NR x -, optionally substituted heteroaryl-NR x -, optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted aryl-O-, optionally substituted heteroaryl -O-; for example, where each optional substituent is independently R y represents the existence of; Q is absent or optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted -substituted (heterocycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, -NR 3 R 4 ,-O-R 3 or -S-R; for example, where each optional substituent is independently R z represents the existence of; W is N or CH; R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted (heteroaryl)alkyl-, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, or -(CH 2 ) m -R 2 for example, where each optional substituent independently represents halo, hydroxy, alkoxy, amino, nitro, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; R 2 is hydrogen, -NR a R b, alkoxy, hydroxy, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; for example, where each optional substituent is independently R y represents the existence of; R 3 and R 4 each independently represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted selected from optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl and optionally substituted (heterocycloalkyl)alkyl; for example , each optional substituent is independently alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, nitro, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, selected from (heterocycloalkyl)alkyl, heteroaryl and (heteroaryl)alkyl; R a and R b each independently selected from hydrogen, alkyl, aminoalkyl, acyl and heterocyclyl; or R a and R b together with the nitrogen to which they are attached form an optionally substituted ring; R x is hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl or cycloalkyl; R y and R z each independently hydroxy, hydroxyalkyl, halo, alkyl, oxo, haloalkyl, alkoxy, alkenyloxy, amino, nitro, cyano, -SH, -S(alkyl), glycinate, ester, thioester, cycloalkyl, hetero selected from cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, and (heteroaryl)alkyl; optionally where hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are further substituted with one or more substituents selected from alkyl, halo, alkenyl, amino, nitro, cycloalkyl and (cycloalkyl)alkyl; or R y and R z together with the atoms to which they are attached form an alkyl chain having 1 to 10 carbon atoms; where 1 to 3 carbon atoms are optionally O, replaced by NH or S; m is 1, 2, or 3; and n is 1 or 2; As defined and described in WO 2017 / 009798 and US 2018 / 0201609, each of which is incorporated herein by reference in its entirety.

[0165] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formulas I-ee-1, I-ee-2, I-ee-3, or I-ee-4, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is selected from phenyl and 5- or 6-membered heteroaryl; Ring B is selected from phenyl and 5- or 6-membered heteroaryl; n is 0, 1, or 2; p is 0, 1, or 2; One of W and X is N, and the other of W and X is C; Y is N or C-R 2 And; R 1 is C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, -CN, -C(R 1a )=NR(OR 1a ), -C(R 1a )=N(R 1a ), -C(O)R 1a , -C(O) 2 R 1a , -C(O)N(R 1a ) 2 ,-NO 2 , -N(R 1a ) 2 , -N(R 1a )C(O)R 1a , -N(R 1a )C(O) 2 R 1a , -N(R 1a )C(O)N(R 1a ) 2 , -N(R 1a )S(O) 2 R 1a ,-OR 1a , -OC(O)R 1a , -OC(O)N(R 1a ) 2 ,-SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)N(R 1a ) 2 , and -S(O) 2 N(R 1a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl and 3- to 6-membered saturated heterocyclyl have one or more R 10 or two R 1 The substituents, together with the atoms between them, form C 5~7 form a cycloalkyl or saturated 5- to 7-membered heterocyclic ring, where this C 5~7 A cycloalkyl or saturated 5- to 7-membered heterocyclic ring has one or more R 15 has been replaced as necessary; R 1a is independently for each existence, H, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 selected from alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl, where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl include one or more R 10 are independently substituted as necessary; R 10 is independently in each existence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, -CN, -C(R 10a )=NR(OR 10a ), -C(R 10a )=N(R 10a ), -C(O)R 10a , -C(O) 2 R 10a , -C(O)N(R 10a ) 2 ,-NO 2 , -N(R 10a ) 2 , -N(R 10a )C(O)R 10a , -N(R 10a )C(O) 2 R 10a , -N(R 10a )C(O)N(R 10a ) 2 , -N(R 10a )S(O) 2 R 10a ,-OR 10a , -OC(O)R 10a , -OC(O)N(R 10a ) 2 ,-SR 10a , -S(O)R 10a , -S(O) 2 R 10a , -S(O)N(R 10a ) 2 , and -S(O) 2 N(R 10a ) 2 selected from; R 10a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 alkyl optionally substituted with one or more halo; R 15 is independently in each existence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, -CN, -C(R 15a )=NR(OR 15a ), -C(R 15a )=N(R 15a ), -C(O)R 15a, -C(O) 2 R 15a , -C(O)N(R 15a ) 2 ,-NO 2 , -N(R 15a ) 2 , -N(R 15a )C(O)R 15a , -N(R 15a )C(O) 2 R 15a , -N(R 15a )C(O)N(R 15a ) 2 , -N(R 15a )S(O) 2 R 15a ,-OR 15a , -OC(O)R 15a , -OC(O)N(R 15a ) 2 ,-SR 15a , -S(O)R 15a , -S(O) 2 R 15a , -S(O)N(R 15a ) 2 , and -S(O) 2 N(R 15a ) 2 selected from; R 15a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 alkyl optionally substituted with one or more halo; R 2 H, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halo, -CN, -C(R 2a )=NR(OR 2a ), -C(R 2a )=N(R 2 ), -C(O)R 2a , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 ,-NO 2 , -N(R 2a ) 2 , -N(R 2a )C(O)R 2a , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 , -N(R 2a )S(O) 2 R 2a ,-OR 2a , -OC(O)R 2a , -OC(O)N(R 2a ) 2 ,-SR 2a , -S(O)R 2a , -S(O) 2 R 2a , -S(O)N(R 2a ) 2 , and -S(O) 2 N(R 2a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl have one or more R 20 has been replaced as necessary; R 2a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 Alkyl, at each occurrence, has one or more R 20 are independently substituted as necessary; R 20 is independently in each existence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, 3- to 7-membered saturated heterocyclyl, halo, -CN, -C(R 20a )=NR(OR 20a ), -C(R 20a )=N(R 20a ), -C(O)R 20a , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 ,-NO 2 , -N(R 20a ) 2 , -N(R 20a )C(O)R 20a , -N(R 20a )C(O) 2 R 20a , -N(R 20a )C(O)N(R 20a ) 2 , -N(R 20a )S(O) 2 R 20a ,-OR 20a , -OC(O)R 20a , -OC(O)N(R 20a ) 2 ,-SR 20a , -S(O)R 20a , -S(O) 2 R 20a , -S(O)N(R 20a ) 2 , and -S(O) 2 N(R 20a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl and 3- to 7-membered saturated heterocyclyls have one or more R 25 are independently substituted as necessary; R 20a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 Alkyl is R 25 has been replaced as necessary; R 25 is halo and -OR 25a selected from; R 25a is H and C 1~6 selected from alkyl; R 3 is C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, -CN, -C(R 3a )=NR(OR 3a ), -C(R 3a )=N(R 3a ), -C(O)R 3a , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 ,-NO 2 , -N(R 3a ) 2 , -N(R 3a )C(O)R 3a , -N(R 3a )C(O) 2 R 3a , -N(R 3a )C(O)N(R 3a ) 2 , -N(R 3a )S(O) 2 R 3a ,-OR 3a , -OC(O)R 3a , -OC(O)N(R 3a ) 2 ,-SR 3a , -S(O)R 3a , -S(O) 2 R 3a , -S(O)N(R 3a ) 2 , and -S(O) 2 N(R 3a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl and 3- to 6-membered saturated heterocyclyl have one or more R 30 has been replaced as necessary; R 3a is independently for each existence, H, C 1~6 selected from alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, where this C 1~6 Alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl have one or more R 30 are independently substituted as necessary; R 30 is independently in each existence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, -CN, -C(R 30a )=NR(OR 30a ), -C(R 30a )=N(R 30a ), -C(O)R 30a , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 ,-NO 2 , -N(R 30a ) 2 , -N(R 30a )C(O)R 30a , -N(R 30a )C(O) 2 R 30a , -N(R 30a )C(O)N(R 30a ) 2, -N(R 30a )S(O) 2 R 30a ,-OR 30a , -OC(O)R 30a , -OC(O)N(R 30a ) 2 ,-SR 30a , -S(O)R 30a S(O) 2 R 30a , -S(O)N(R 30a ) 2 , and -S(O) 2 N(R 30a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carboyclyl, 3- to 6-membered heterocyclyl have one or more R 35 are independently substituted as necessary; R 30a is independently at each occurrence, H and C 1~4 selected from alkyl, where C 1~4 Alkyl has one or more R 35 has been replaced as necessary; R 35 is independently at each occurrence, halo and -OR 35a selected from; R 35a is independently at each occurrence, H and C 1~6 selected from alkyl; R 4 is H, halo, C 1~6 Alkyl, N(R 4a ) 2 , and -OR 4a selected from; and R 4a is independently at each occurrence, H and C 1~6 selected from alkyl; As defined and described in WO 2016 / 011390 and US 2017 / 0204093, each of which is incorporated herein by reference in its entirety.

[0166] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and thus the formula I-ff-1, I-ff-2, I-ff-3, or I-ff-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is selected from phenyl and 5- or 6-membered heteroaryl; Ring B is selected from phenyl and 5- or 6-membered heteroaryl; Ring C is a 3- to 6-membered carbocyclyl, n is 1, 2 or 3; p is 0, 1, or 2; One of W and X is N, and the other of W and X is C; Y is N or C-R 2 And; R 1 is C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, halo, -CN, -C(R la )=NR(OR la ), -C(R la )=N(R la ), -C(O)R la , -C(O) 2 R la , -C(O)N(R la ) 2 ,-NO 2 , -N(R la ) 2 , -N(R la )C(O)R la , -N(R la )C(O) 2 R la , -N(R la )C(O)N(R la ) 2 , -N(R la )S(O) 2 R la ,-OR la , -OC(O)R la , -OC(O)N(R la ) 2 ,-SR la , -S(O)R la , -S(O) 2 R la , -S(O)N(R la ) 2 , and -S(O) 2 N(R la ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, and C 2~6 Alkynyl has one or more R 10 has been replaced as necessary; R la is independently H or C at each occurrence 1~6 selected from alkyl, where this C 1~6 Alkyl, at each occurrence, has one or more R 10 are independently substituted as necessary; R 10 is independently at each occurrence: halo, -CN, -C(R 10a )=NR(OR) 10a , -C(R 10a )=N(R 10a ), -C(O)R 10a , -C(O) 2 R 10a , -C(O)N(R 10a ) 2 ,-NO 2 , -N(R 10a ) 2 , -N(R 10a )C(O)R 10a , -N(R 10a )C(O) 2 R 10a , -N(R 10a )C(O)N(R 10a ) 2 , -N(R 10a )S(O) 2 R 10a ,-OR 10a , -OC(O)R 10a , -OC(O)N(R 10a ) 2 ,-SR 10a , -S(O)R 10a , -S(O) 2 R 10a , -S(O)N(R 10a ) 2 , and -S(O) 2 N(R 10a ) 2 selected from; R 10a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1 - 6 alkyl optionally substituted with one or more halo; R is H, C 1 ~ 6 Alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 Alkynyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halo, -CN, -C(R 2a )=NR(OR 2a ), -C(R 2a )=N(R 2a ), -C(O)R 2a , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 ,-NO 2 , -N(R 2a ) 2 , -N(R 2a )C(O)R 2a , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 , -N(R 2a )S(O) 2 R 2a ,-OR 2a , -OC(O)R 2a , -OC(O)N(R 2a ) 2 ,-SR 2a , -S(O)R 2a , -S(O) 2 R 2a , -S(O)N(R 2a ) 2 , and -S(O) 2 N(R 2a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2 ~ 6 Alkynyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl have one or more R 20 has been replaced as necessary; R 2a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 alkyl is optionally independently substituted at each occurrence with one or more R20; R20 is independently at each occurrence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, 3- to 7-membered saturated heterocyclyl, halo, -CN, -C(R 20a )=NR(OR 20a ), -C(R 20a )=N(R 20a ), -C(O)R 20a , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 ,-N0 2 , -N(R 20a ) 2 , -N(R 20a )C(O)R 20a , -N(R 20a )C(O) 2 R 20a , -N(R 20a )C(O)N(R 20a ) 2 , -N(R 20a )S(O) 2 R 20a ,-OR 20a , -OC(O)R 20a , -OC(O)N(R 20a ) 2 ,-SR 20a , -S(O)R 20a , -S(O) 2 R 20a , -S(O)N(R 20a ) 2 , and -S(O) 2 N(R 20a ) 2 and where this C 1~6 Alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 Alkynyl, C 3~7 Cycloalkyl and 3- to 7-membered saturated heterocyclyls have one or more R 25 are independently substituted as necessary; R 20a is independently at each occurrence, H and C 1~6 selected from alkyl, where this C 1~6 Alkyl is R 25 has been replaced as necessary; R 25 is halo and -OR 25a selected from; R 25a is H and C 1~6 selected from alkyl; R is C 1~6 Alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 Alkynyl, C 3~6 Cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, -CN, -C(R 3a )=NR(OR 3a ), -C(R 3a )=N(R 3a ), -C(O)R 3a , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 ,-NO 2 , -N(R 3a ) 2 , -N(R 3a )C(O)R 3a , -N(R 3a )C(O) 2 R 3a , -N(R 3a )C(O)N(R 3a ) 2 , -N(R 3a )S(O) 2 R 3a ,-OR 3a , -OC(O)R 3a , -OC(O)N(R 3a ) 2 ,-SR 3a , -S(O)R 3a , -S(O) 2 R 3a , -S(O)N(R 3a ) 2 , and -S(O) 2 N(R 3a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2 ~ 6 Alkynyl, C 3~6 Cycloalkyl, and 3- to 6-membered saturated heterocyclyl have one or more R 30 has been replaced as necessary; R 3a is independently for each existence, H, C 1~6 selected from alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, where this C 1~6 Alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl have one or more R at each occurrence. 30 are independently substituted as necessary; R 30 is independently at each occurrence, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, -CN, -C(R 30a )=NR(OR 30a ), -C(R 30a )=N(R 30a ), -C(O)R 30a , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 ,-NO 2 , -N(R 30a ) 2 , -N(R 30a )C(O)R 30a , -N(R 30a )C(O) 2 R 30a , -N(R 30a )C(O)N(R 30a ) 2 , -N(R 30a )S(O) 2 R 30a ,-OR 30a , -OC(O)R 30a , -OC(O)N(R 30a ) 2 ,-SR 30a , -S(O)R 30a , -S(O) 2 R 30a , -S(O)N(R 30a ) 2 , and -S(O) 2 N(R 30a ) 2 and where this C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl has one or more R 35 are independently substituted as necessary; R 30a is independently at each occurrence, H and C 1~4 selected from alkyl, where C 1~4 Alkyl has one or more R 35 has been replaced as necessary; R 35 is independently at each occurrence, halo and -OR 35a selected from; and R 35a is independently at each occurrence, H and C 1~6 selected from alkyl; As defined and described in WO 2017 / 127430, which is incorporated herein by reference in its entirety.

[0167] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-gg-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: HET is 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, where the heteroaryl is attached to the pyridinyl group of the compound of formula (I) by a nitrogen ring atom in the heteroaryl. and this heteroaryl has 0 to 2 R b is replaced with; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each of which is R a is replaced with; R 3 is C 2~3 Alkyl, C 2~3 Fluoroalkyl, C 3~4 hydroxyalkyl, or a cyclic group, where the cyclic group is C 3~6 selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is F, -OH, C 1~2 alkyl, and -CH 2 CHF 2substituted with 0 to 2 substituents independently selected from; R a teeth: (i) H, F, C 1 ,-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, -(CH 2 ) 1~3 NHR y ,-(CH 2 ) 1~3 NR y R y ,-CH 2 CH(OH)(phenyl), -CH(CH 2 OH)(phenyl), -CH 2 CH(OH)CH 2 (phenyl), -CH 2 CH(OH)CH 2 O(methoxyphenyl), -CH 2 CH(NH 2 )CH 2 (phenyl), -(CH 2 CH 2 O) 4 H, -(CH 2 ) 1~3 O(C 1~3 alkyl), -CH 2 CH(OH)CH 2 O(C 1~3 alkyl), -CH 2 C(O)(C 1~3 alkyl), -CH 2 C(O)NR y R y ,-(CH 2 ) 1~3 NR y C(O)(C 1~3 alkyl), -CH 2 C(O)O(C 1~3 alkyl), -C(O)NH 2 ,-CH 2 NR y C(O)NH 2 ,-(CH 2 ) 1~2 NR y C(O)O(C 1~2 alkyl), -(CR y R y ) 1~5 OC(O)CH 2 NR y R y ,-CH 2 CH 2 S(O) 2 CH 3 ,-CH 2 S(O) 2 (C 1~3 alkyl), -CH 2 S(O) 2 (phenyl), or -NH(aminocyclohexyl); or (ii) -(CH 2 ) 0~3 R z or -(CH 2 ) 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 F, -CN, -OH, -NR y R y ,C 1~3 Alkyl, C 1~3 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)CH 2 (C 3~6 cycloalkyl), -C(O)O(C 1~4 alkyl), -NH(C 1~4 alkyl), -NH(C 1~3 Fluoroalkyl), -NHC(O)CH 3 , -NHC(O)O(C 1~3 alkyl), -NHC(O)OC(CH 3 ) 3 , -S(O) 2 (C 1~3 alkyl), -OS(O) 2 (C 1~3 alkyl), methyloxadiazolyl, and pyrimidinyl; Each R b are independently H, Cl, -CN, -NH 2 , and -C(O)NH 2 wherein the heteroaryl is attached to the pyridinyl group by 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 herein by reference in its entirety.

[0168] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and thereby the formula I-hh-1, I-hh-2, I-hh-3, or I-hh-4: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X 1 ,X 2 and X 3 are each independently CR 2 or N; A is O, S, S(O) or S(O) 2 And; Z 1 optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ( heterocycloalkyl)alkyl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl)alkyl-, optionally substituted aryl oxy-, optionally substituted heteroaryloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted cycloalkyloxy-, optionally substituted aryl-NR '-, optionally substituted heteroaryl-NR'-, optionally substituted heterocycloalkyl-NR'-, optionally substituted cycloalkyl-NR'-, optionally substituted Substituted aryl-S-, optionally substituted heteroaryl-S-, optionally substituted heterocycloalkyl-S-, optionally substituted cycloalkyl-S-, optionally substituted optionally substituted (cycloalkyl)alkyl-NR'-, optionally substituted aralkyl-NR'-, optionally substituted (heterocycloalkyl)alkyl-NR'-, optionally substituted Substituted heteroaralkyl-NR'-, optionally substituted (cycloalkyl)alkyl-S-, optionally substituted aralkyl-S-, optionally substituted (heterocycloalkyl) Alkyl-S-, optionally substituted heteroaralkyl-S-, optionally substituted (cycloalkyl)alkyl-O-, optionally substituted aralkyl-O-, optionally substituted Substituted (heterocycloalkyl)alkyl-O-, optionally substituted heteroaralkyl-O-; for example, where each optional substituent is independently R x represents the existence of; Z 2is absent or optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted optionally substituted aryloxy-, optionally substituted heteroaryloxy-, optionally substituted cycloalkyloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted (cycloalkyl)alkyl-, optionally substituted aralkyl-, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl)alkyl-NR”-, optionally substituted aralkyl-NR”-, optionally substituted (heterocycloalkyl)alkyl-NR”-, optionally substituted heteroaralkyl-NR”-, optionally substituted (cycloalkyl)alkyl-O-, optionally substituted aralkyl-O-, optionally substituted (heterocycloalkyl)alkyl-O -, optionally substituted heteroaralkyl-O-, optionally substituted (cycloalkyl)alkyl-S-, optionally substituted aralkyl-S-, optionally substituted (heterocycloalkyl)alkyl-S- or optionally substituted heteroaralkyl-S-; for example, where each optional substituent is independently R y represents the existence of; Z 3 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl oxy-, optionally substituted heteroaryloxy-, optionally substituted cycloalkyloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted (cycloalkyl )alkyl-, optionally substituted aralkyl-, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl) )-NR'"-, optionally substituted aryl-NR'"-, optionally substituted heteroaryl-NR'"-, optionally substituted heterocycloalkyl-NR'" -, optionally substituted aryl-S-, optionally substituted heteroaryl-S-, optionally substituted cycloalkyl-S-, optionally substituted heterocycloalkyl -S-, optionally substituted (cycloalkyl)alkyl-NR'"-, optionally substituted aralkyl-NR'"-, optionally substituted (heterocycloalkyl)alkyl- NR'"-, optionally substituted heteroaralkyl-NR'"-, optionally substituted (cycloalkyl)alkyl-O-, optionally substituted aralkyl-O-, optionally optionally substituted (heterocycloalkyl)alkyl-O-, optionally substituted heteroaralkyl-O-, optionally substituted (cycloalkyl)alkyl-S-, optionally substituted aralkyl-S-, optionally substituted (heterocycloalkyl)alkyl-S-, or optionally substituted heteroaralkyl-S-; for example, where each optional substituent is independently, R z represents the existence of; Each R 2 are independently hydrogen, alkyl, haloalkyl, halo, cyano, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl-, optionally optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, -NR a R b ,-O-R 3 and -S-R 3 selected from; for example, where each optional substituent is independently alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, -SH, -S(alkyl), cyano, amido, amino, carboxylate , glycinate, alaninate, oxo, aryl, cycloalkyl, heterocycloalkyl or heteroaryl; each of R', R'' and R''' is independently selected from hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl and cycloalkyl; R x ,R y and R z each independently represents alkyl, alkenyl, alkynyl, halo, hydroxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, -SH, -S(alkyl), cyano, amide, carboxylic acid, carboxylate, ester, thioester, Alkoxycarbonyl, -C(O)NH(alkyl), oxo, cycloalkyl, cycloalkyloxy, (cycloalkyl)alkyl-, aryl, aralkyl-, heterocycloalkyl, heteroaryl, (heterocycloalkyl)alkyl-, hetero Aralkyl-,-NR a R b ,-O-R 4 or -S-R 4 optionally, where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are halo, haloalkyl, amino, hydroxy, alkyl, cyano, nitro, alkenyl, aminoalkyl, hydroxyalkyl, and haloalkoxy further substituted with one or more substituents selected from; R a and R b each independently hydrogen, alkyl, aminoalkyl, acyl, aminoacyl, halo, haloalkyl, hydroxy, haloalkoxy, hydroxyalkyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl -, (heterocycloalkyl)alkyl-, aralkyl-, and (heteroaryl)alkyl-; optionally, where the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are alkyl, halo, alkenyl , cyano, hydroxy, hydroxyalkyl, alkoxy, amino and nitro; or R a and R b together with the atoms to which they are attached form a 3- to 8-membered optionally substituted ring; and R 3 and R 4 each independently represents hydrogen, alkyl, aminoacyl, phosphate, phosphonate, alkylphosphate, alkoxycarbonyl, cycloalkyl, (cycloalkyl)alkyl-, aryl, heteroaryl, heterocycloalkyl, aralkyl-, heteroaralkyl-, and (heterocyclo alkyl)alkyl-; As defined and described in WO 2017 / 009806 and US 2018 / 0208605, each of which is incorporated herein by reference in its entirety.

[0169] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, formula I-ii-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is CR or N; A is O, S, SO 2 , SO, -NRC(O), -NRSO 2 , or N(R); or A does not exist; R 3 -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 ,-SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 ,-NRSO 2 R, or -N(R) 2 is; or A is -NRC(O), -NRSO 2 , or if N(R); R and R 3 is a 3- to 7-membered heterocyclic ring, each having, together with the atoms to which it is attached, 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or may form a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of these may be optionally substituted. has been; X’ is CR or N; Ring Z is a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or independently selected from nitrogen, oxygen, and sulfur a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms, each of which is optionally substituted; R 1 -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 ,-SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R)2 , -NRC(O)R, -NRC(O)N(R) 2 ,-NRSO 2 R, or -N(R) 2 And; R a is absent or -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 ,-SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 ,-NRSO 2 R, or -N(R) 2 And; Ring Y is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 2 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2 -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 ,-SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 ,-NRSO 2 R, or -N(R) 2 And; R b is absent or -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 ,-SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 ,-NRSO 2 R, or -N(R) 2 And; Each R is independently hydrogen, C 1~6 aliphatic, C 3~10 Aryl, 3- to 8-membered saturated or partially unsaturated carbocyclic ring, 3- to 7-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of these optionally has been replaced; or Two R groups on the same atom together with the atom to which they are attached form a C 3~10 Aryl, 3- to 8-membered saturated or partially unsaturated carbocyclic ring, 3- to 7-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which optionally are replaced accordingly; As defined and described in WO 2016 / 081679 and US 2016 / 0145252, each of which is incorporated herein by reference in its entirety.

[0170] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the expressions I-jj-1 or I-jj-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is NH or O; b is 0 or 1; n is 0, 1, 2, 3 or 4; R 1 and R 2 are independently H, (C 1 ~C 4 )alkyl and heterocyclyl, or R 1 and R 2 contain 3 to 8 carbon atoms together with the nitrogen to which they are attached, and in addition to this nitrogen one or two further heteroatoms selected from N, O and S may form monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycles optionally containing R a optionally substituted with one or more substituents selected from; R 3 is (C 1 ~C 4 ) alkyl, where two adjacent alkyl groups may together form a bridging moiety of 3 to 6 carbon atoms; R 4 is absent or halo or O b (C 1 ~C 4 ) is alkyl; R 5 is C 1 ~C 4 Alkyl and C 2 ~C 4 selected from alkenyl, these are R b optionally substituted with one or more substituents selected from; R 6 is absent, halo, or O(C 1 ~C 4 ) is alkyl; R a is halo, oxo, OH, O b (C 1 ~C 4 )alkyl, CF 3 ,S.O. 2 (C 1 ~C 4 )alkyl, or heterocyclyl, which includes F, and (C 1 ~C 4 ) optionally substituted with one or more substituents independently selected from alkyl; and R b are independently OH, halo, O b (C 1 ~C 4 ) alkyl, and CN; As defined and described in WO 2016 / 053769 and US 2017 / 0247388, each of which is incorporated herein by reference in its entirety.

[0171] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-kk-1 or I-kk-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: B is CH, N or S; D is CH or N; E is CH or N; F is CH or N; G is CH or N; and J is , C or N, where B is S, D is CH, E is N, F is CH, G is N, and J is C; X is O, S, CH 2 or N; m is 0 or 1; n is 0, 1 or 2; Ring A is pyridinyl, pyrazolyl, thiophenyl, furanyl or phenyl; R 1 are independently, (C 1 ~C 4 )alkyl, pyrimidine, piperidine and phenyl, each of which is selected from (C 1 ~C 4 )alkyl, OH, halo, O(C 1 ~C 4 )alkyl, methylpiperidine, S(O) 2 R c ,C(O)N(R b ) 2 , or C(O)O(C 1 ~C 4 ) optionally substituted with alkyl; R 2 is absent or H, and R 3 are independently :(C 1 ~C 4 )alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, each of which is selected from halo, OH, oxo, N(R b ) 2 , oxopyrrolidinyl, or morpholinyl, or R 2 and R 3 together with the nitrogen to which they are attached may form piperazine or morpholine, each optionally substituted with oxo; R 4 are independently H or methyl; R b are independently H and (C 1 ~C 4 ) alkyl; and R c is methyl; As defined and described in WO 2016 / 144844 and US 2018 / 0051027, each of which is incorporated herein by reference in its entirety.

[0172] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , which gives the formula I-kk’-1 or I-kk’-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and the variables A, B, D, E, F, G, J, X, R 1 ,R 2 ,R 3 and n are as defined and described in WO 2016 / 144844 and US 2018 / 0051027, each of which is incorporated herein by reference in its entirety. Such IRAK4 inhibitors are well known to those skilled in the art and are described in Smith et al., Bioorg.Med.Chem., 2017, 27(12):2721-2726 and Lim et al., ACS Med.Chem.Lett. .,2015,6(6):683-688.

[0173] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , which gives the formula I-ll-1 or I-ll’-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is aryl or heterocyclyl; n is 0, 1, 2, 3 or 4; R 1 are independently :(C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, heterocyclyl, CF 3 ,CHF 2 , CN, halo, and this alkyl, cycloalkyl and heterocyclyl is selected from halo, OH, CH 3 , and OCH 3 has been replaced as necessary; R 2 is H and R 3 are independently :(C 1 ~C 6 )alkyl, (C 3 ~C 8 )cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R b ) 2 , or optionally substituted with morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, which R a optionally substituted with one or more substituents selected from; R a are independently, (C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, CF 3 ,CHF 2 , OH, halo and NH 2 and this alkyl is selected from (C 3 ~C 6 )cycloalkyl and CF 3 are replaced as necessary; and R b are independently H and (C 1 ~C 4 ) alkyl; As defined and described in WO 2016 / 144847 and US 2018 / 0051029, each of which is incorporated herein by reference in its entirety.

[0174] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , which gives the formula I-mm-1 or I-mm’-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is aryl or heterocyclyl; n is 0, 1, 2, 3 or 4; R 1 are independently :(C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, heterocyclyl, CF 3 ,CHF 2 , CN and halo, this alkyl, cycloalkyl and heterocyclyl is selected from halo, OH, CH 3 , and OCH 3 has been replaced as necessary; R 2 is H and R 3 are independently :(C 1 ~C 6 )alkyl, (C 3 ~C 8 )cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R b ) 2 , or optionally substituted with morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, which R a optionally substituted with one or more substituents selected from; R a are independently, (C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, CF 3 ,CHF 2 , OH, halo and NH 2 This alkyl selected from (C 3 ~C 6 )cycloalkyl or CF 3 are replaced as necessary; and R b are independently H and (C 1 ~C 4 ) alkyl; As defined and described in WO 2016 / 144846 and US 2018 / 0051028, each of which is incorporated herein by reference in its entirety.

[0175] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , which gives the formula I-nn-1 or I-nn’-2, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is aryl or heterocyclyl; n is 0, 1, 2, 3 or 4; R 1 are independently :(C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, heterocyclyl, CF 3 ,CHF 2 , CN, halo, and this alkyl, cycloalkyl and heterocyclyl is selected from halo, OH, CH 3 , and OCH 3 has been replaced as necessary; R 2 is H and R 3 are independently :(C 1 ~C 6 )alkyl, (C 3 ~C 8 )cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R b ) 2 , or optionally substituted with morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, which R aoptionally substituted with one or more substituents selected from; R a are independently, (C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, CF 3 ,CHF 2 , OH, halo and NH 2 and this alkyl is selected from (C 3 ~C 6 )cycloalkyl and CF 3 are replaced as necessary; and R b are independently H and (C 1 ~C 4 ) alkyl; As defined and described in WO 2016 / 144848 and US 2018 / 0051030, each of which is incorporated herein by reference in its entirety.

[0176] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] which gives the formula I-oo-1 or I-oo’-2, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is aryl or heterocyclyl; n is 0, 1, 2, 3 or 4; R 1 are independently :(C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, heterocyclyl, CF 3 ,CHF 2 , CN, halo, and this alkyl, cycloalkyl and heterocyclyl is selected from halo, OH, CH 3 , and OCH 3 has been replaced as necessary; R 2 is H and R 3 are independently :(C 1 ~C 6 )alkyl, (C 3 ~C 8 )cycloalkyl and heterocyclyl, each containing one or more halo, OH, N(R b ) 2 , or optionally substituted with morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, which R a optionally substituted with one or more substituents selected from; R a are independently, (C 1 ~C 4 )alkyl, (C 3 ~C 6 )cycloalkyl, CF 3 ,CHF 2 , OH, halo and NH 2 and this alkyl is selected from (C 3 ~C 6 )cycloalkyl and CF 3 are replaced as necessary; and R b are independently H and (C 1 ~C 4 ) alkyl; As defined and described in WO 2016 / 144849 and US 2018 / 0051035, each of which is incorporated herein by reference in its entirety.

[0177] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and IRAK4. [ka] and, thereby, the formula I-pp-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; Ring B is [ka] and here [ka] represents the part where this ring is fused to the pyrimidine ring, and # represents -L 2 (R 4 ) P -R X And ;R 1 and R 1’ Each of the -R 2 , halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -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, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from; or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a fused, spirofused or bridged bicyclic ring; Each Cy is independently a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from ~10-membered saturated or partially unsaturated heterocyclic rings; each R is independently hydrogen or an optionally substituted group; , this optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 is independently, Ci- 6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur; Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1 ~ 6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur; R x is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -NH[Ar], -OR, or -S(O) 2 N(R) 2 And; R z is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -NH[Ar], -OR, or -S(O) 2 N(R) 2 And; [Ar] is phenyl or a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where [Ar] is R for m examples 1 has been replaced by; L 1 is a covalent bond or C 1 ~ 6 is a divalent hydrocarbon chain in which the one or two methylene units of this chain are -N(R)-, -N(R)C(O)-, -C(O)N(R )-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - independently replaced as necessary by; L 2 is a covalent bond or C 1 ~ 6 divalent hydrocarbon chain, where one or two methylene units of this chain are -N(R)-, -N(R)C(O)-, -C(O)N( R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - independently replaced as necessary by; m is 0~4; n is 0~4; and p is 0~2; as defined and described in WO 2017 / 004133, each of which is incorporated herein by reference in its entirety.

[0178] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and IRAK4. [ka] and, thereby, the formula I-qq-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Y is N or C-R x And; Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; R 1 and R v Each of the -R 2 , halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -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, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from; or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a fused, spirofused or bridged bicyclic ring; Each Cy is independently a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from ~10-membered saturated or partially unsaturated heterocyclic rings; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings with 1 to 4 heteroatoms independently selected from sulfur, or: two R groups on the same nitrogen have between them a 4- to 7-membered saturated, partially unsaturated, or forming a heteroaryl ring; Each R 2 is independently, Ci- 6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from sulfur; R x and R y Each of is independently hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -H[Ar], -OR, or -S(O) 2 N(R) 2 is; or R x and R y together with the intervening atoms are a 4- to 7-membered partially unsaturated carbocyclic ring, or 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a partially unsaturated heterocyclic ring having; R z is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -NH[Ar], -OR, or -S(O) 2 N(R) 2 And; [Ar] is phenyl or a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the [Ar] , R for m examples r has been replaced by; L 1 is a covalent bond or Ci- 6 divalent hydrocarbon chain, where one or two methylene units of this chain are -N(R)-, -N(R)C(O)-, -C(O)N( R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - independently replaced as necessary by; m is 0~4; and n is 0 to 4; as defined and described in WO 2017 / 004134, each of which is incorporated herein by reference in its entirety.

[0179] In certain embodiments, the invention provides that IRAK is an IRAK inhibitor [ka] and thereby the formula I-rr-1, I-rr-2, or I-rr-3: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide or CN; R 1 is H, aliphatic or heteroaliphatic; Or R and R 1 together with the atoms to which they are attached form a heterocyclyl ring; R 2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or aromatic aliphatic; Each R 3 are independently H, aliphatic, halogen, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxy, nitro, cyano, carboxyl, carboxyl ester, acyl, amide , amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate; y is 1~6; As defined and described in WO 2016 / 172560 and US 2016 / 0311839, each of which is incorporated herein by reference in its entirety.

[0180] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-ss-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: A is [ka] And; X is N or C-R 7 And; R is hydrogen, R 1 , halogen, cyano, nitro, -OR 1 , -C(=O)-R 1 , -C(=O)O-R 1 , -C(=O)NR 11 -R 1 , -S(=O) 2 -R 1 ,-NR 11 C(=O)-R 1 ,-NR 11 C(=O)NR 11 R 11 ,-NR 11 C(=O)O-R 1 ,-NR 11 S(=O) 2 R 1 or -NR 11 R 11 And; R 1 is 0 to 4 R 1a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced with 2~6 alkenyl, 0 to 3 R 1a C replaced with 2~6 Alkynyl, 0 to 3 R 1a C replaced with 3~10 Cycloalkyl, 0 to 3 R 1a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 1a is a 5- to 10-membered heteroaryl substituted with; R 1a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; R 2 is 0 to 4 R 2a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 1 to 4 R 2a a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 4 R 2a is a 5- to 10-membered heteroaryl substituted with; R 2a are hydrogen, =O, halo, OCF, independently in each occurrence 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 2 R a -(CH 2 ) r - selected from 5- to 7-membered heterocycles or heteroaryls; R 3 is 0 to 3 R 3a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced with 2~6 alkenyl, 0 to 3 R 3a C replaced with 2~6 Alkynyl, 0 to 3 R 3a C replaced with 3~10 Cycloalkyl, 0 to 3 R 3a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3a 5- to 10-membered heterocyclyl, or containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 3 R 3a is a 5- to 10-membered heteroaryl substituted with; R 3a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 )r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 1 R a -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; R 4 and R 5 are independently hydrogen, 0 to 1 R f C replaced with 1~4 Alkyl, 0 to 3 R d (CH 2 )-phenyl, and carbon atoms, as well as N, O, and S(O) p -(CH 2 )-selected from 5- to 7-membered heterocycles; R 6 and R 7 are, independently in each occurrence, hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O) 2 R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -Selected from 5- to 7-membered heterocycle or heteroaryl, provided that R 6 and R 7 and both cannot become hydrogen; R 11 is hydrogen, R e , 0~1 R f C replaced with 1~4 Alkyl, 0 to 3 R d CH substituted with 2 -phenyl, or carbon atoms, and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R d -(CH 2 )-5- to 7-membered heterocycle; or R 11 and another R on the same nitrogen atom 11 ,R 1 , or R 2 may be taken together to form an optionally substituted heterocycle; R a is hydrogen, F, Cl, Br, OCF 3 , C.F. 3 ,CHF 2 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 ,-(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~1 R f C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; or two R's adjacent or on the same carbon atom a is the formula -O-(CH 2 ) n -O-, or -O-CF 2 forming a cyclic acetal of -O-, where n is selected from 1 or 2; R b is hydrogen, R e , 0~2 R d C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced with 3~6 cycloalkyl, or 0 to 3 R d (CH 2 ) r - is phenyl; R c is 0 to 1 R f C replaced with 1~6 Alkyl, C 3~6 cycloalkyl, or 0 to 3 R f (CH 2 ) r - is phenyl; R d is hydrogen, F, Cl, Br, OCF 3 , C.F. 3 ,CN,NO 2 ,-OR e ,-(CH 2 ) r C(O)R c ,-NR e R e ,-NR e C(O)OR c ,C 1~6 Alkyl, or 0 to 3 R f (CH 2 ) r - is phenyl; R e is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, and 0 to 3 R f (CH 2 )r - selected from phenyl; R f is hydrogen, halo, NH 2 , OH, or O(C 1~6 alkyl); p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; As defined and described in WO 2013 / 106612 and US 2015 / 0011532, each of which is incorporated herein by reference in its entirety.

[0181] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-tt-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: A is a triazole optionally substituted with 0 to 2 R; X is N or C-R 7 And; R is hydrogen, R’, halogen, cyano, nitro, -OR 1 , -C(=O)-R 1 , -C(=O)O-R 1 , -C(=O)NR 11 -R 1 , -S(=O) 2 -R 1 ,-NR 11 C(=O)-R’, -NR 11 C(=O)NR 11 R 1 ,-NR 11 C(=O)O-R’, -NR 11 S(=O) 2 R 1 or -NR 11 R 1 And; R 1 is 0 to 4 R 1a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced with 2~6 alkenyl, 0 to 3 R 1a C replaced with 2~6 Alkynyl, 0 to 3 R 1a C replaced with 3~10 Cycloalkyl, 0 to 3 R 1a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 1a is a 5- to 10-membered heteroaryl substituted with; R 1a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(C)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; R 2 is 0 to 4 R 2a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 1 to 4 R 2a a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 4 R 2a is a 5- to 10-membered heteroaryl substituted with; R 2a are hydrogen, =O, halo, OCF, independently in each occurrence 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, 0, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 2 R a -(CH 2 ) r - selected from 5- to 7-membered heterocycles or heteroaryls; R 3 is 0 to 3 R 3a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced with 2~6 alkenyl, 0 to 3 R 3a C replaced with 2~6 Alkynyl, 0 to 3 R 3a C replaced with 3~10 Cycloalkyl, 0 to 3 R 3a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3’ 5- to 10-membered heterocyclyl, or containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 3 R 3a is a 5- to 10-membered heteroaryl substituted with; R 3a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) rC(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 1 R a -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; R 4 and R 5 are independently hydrogen, 0 to 1 R f C replaced with 1~4 Alkyl, 0 to 3 R d (CH 2 )-phenyl, and carbon atoms, as well as N, O, and S(O) p -(CH 2 )-selected from 5- to 7-membered heterocycles; R 6 and R 7 are, independently in each occurrence, hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -Selected from 5- to 7-membered heterocycle or heteroaryl, provided that R 6 and R 7 and both cannot become hydrogen; R 11 is hydrogen, R e , 0~1 R f C replaced with 1~4 Alkyl, 0 to 3 R d CH substituted with 2 -phenyl, or carbon atoms, and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R d -(CH 2 )-5- to 7-membered heterocycle; or R 11 and another R on the same nitrogen atom 11 ,R 1 , or R 2 may be taken together to form an optionally substituted heterocycle; R a is hydrogen, F, Cl, Br, OCF 3 , C.F. 3 ,CHF 2 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~1 R f C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; or two R's adjacent or on the same carbon atom a is the formula -O-(CH 2 ) n -O-, or -O-CF 2 forming a cyclic acetal of -O-, where n is selected from 1 or 2; R b is hydrogen, R e , 0~2 R d C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced with 3~6 cycloalkyl, or 0 to 3 R d (CH 2 ) r - is phenyl; R c is 0 to 1 R f C replaced with 1~6 Alkyl, C 3~6 cycloalkyl, or 0 to 3 R f (CH 2 ) r - is phenyl; R d is hydrogen, F, Cl, Br, OCF 3 , C.F. 3 ,CN,NO 2 ,-OR e ,-(CH 2 ) r C(O)R c ,-NR e R e ,-NR e C(O)OR c ,C 1~6 Alkyl, or 0 to 3 R f (CH 2 ) r - is phenyl; R e is hydrogen, C 1~6Alkyl, C 3~6 cycloalkyl, and 0 to 3 R f (CH 2 ) r - selected from phenyl; R f is hydrogen, halo, NH 2 , OH, or O(C 1~6 alkyl); p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; As defined and described in WO 2013 / 106614 and US 2015 / 0045347, each of which is incorporated herein by reference in its entirety.

[0182] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-uu-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is N or C-R 7 And; R is R 1 , halogen, cyano, nitro, -O-R 1 , -C(=O)-R 1 , -C(=O)O-R 1 , -C(=O)NR 11 -R 1 , -S(=O) 2 -R 1 ,-NR 11 C(=O)-R 1 ,-NR 11 C(=O)NR 11 -R 1 ,-NR 11 C(=O)O-R 1 ,-NR 11 S(=O) 2 -R 1 , or -NR 11 -R 1 And; R 1 is 0 to 4 R 1a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced with 2~6 alkenyl, 0 to 3 R 1a C replaced with 2~6 Alkynyl, 0 to 3 R 1a C replaced with 3~10 Cycloalkyl, 0 to 3 R 1a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 3 R 1a is a 5- to 10-membered heteroaryl substituted with; R 1a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -It is a 5- to 7-membered heterocycle; R 2 is 0 to 4 R 2a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 4 R 2a a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, substituted with 0 to 4 R 2a is a 5- to 10-membered heteroaryl substituted with; R 2a are hydrogen, =O, halo, OCF, independently in each occurrence 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 2 R a -(CH 2 ) r - selected from 5- to 7-membered heterocycles or heteroaryls; R 3 is 0 to 3 R 3a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced with 2~6 alkenyl, 0 to 3 R 3a C replaced with 2~6 Alkynyl, 0 to 3 R 3a C replaced with 3~10 Cycloalkyl, 0 to 3 R 3a C replaced with 6~10 Contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3a or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 3a is a 5- to 10-membered heteroaryl substituted with; R 3a is hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 1 R a -(CH 2 ) r -5- to 7-membered heterocycle or heteroaryl; R 4 and R 5 are independently hydrogen, 0 to 1 R f C replaced with 1~4 Alkyl, 0 to 3 R d (CH 2 )-phenyl, and carbon atoms, as well as N, O, and S(O) p -(CH 2 )-selected from 5- to 7-membered heterocycles; R 6 and R 7 are, independently in each occurrence, hydrogen, =O, F, Cl, Br, OCF 3 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O)R c , -S(O) 2 R c , 0~2 R a C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH 2 ) r -3- to 14-membered carbocycle, or each of carbon atoms and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R a -(CH 2 ) r -Selected from 5- to 7-membered heterocycle or heteroaryl, provided that R 6 and R 7 and both cannot become hydrogen; R 11 is independently in each existence, R e , 0~1 R f C replaced with 1~4 Alkyl, 0 to 3 R d CH substituted with 2 -phenyl, or each carbon atom, and N, O, and S(O) p containing 1 to 4 heteroatoms selected from 0 to 3 R d -(CH 2 )-5- to 7-membered heterocycle or heteroaryl; Alternatively, R 11 and another R on the same nitrogen atom 11 ,R 1 , or R 2 taken together with optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C 1~6 alkyl)piperazinyl; R a is R d ,F,Cl,Br,OCF 3 , C.F. 3 ,CHF 2 ,CN,NO 2 ,-(CH 2 ) r OR b ,-(CH 2 ) r S.R. b ,-(CH 2 ) r C(O)R b ,-(CH 2 ) r C(O)OR b ,-(CH 2 ) r OC(O)R b ,-(CH 2 ) r NR 11 R 11 ,-(CH 2 ) r C(O)NR 11 R 11 ,-(CH 2 ) r NR b C(O)R c ,-(CH 2 ) r NR b C(O)OR c ,-NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 ,-NR b S(O) p R c , -S(O) 2 R c , -S(O) 2 R c , 0~1 R f C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, -(CH 2 ) r -3- to 14-membered carbocycles, or carbon atoms, and N, O, and S(O) p -(CH 2 ) r -Is it a 5- to 7-membered heterocycle; or two R's on adjacent or the same carbon atoms a is the formula -O-(CH 2 ) n -O-, or -O-CF 2 forming a cyclic acetal of -O-, where n is selected from 1 or 2; R b is R c , 0~2 R d C replaced with 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced with 3~6 cycloalkyl, or 0 to 3 R d (CH 2 ) r - is phenyl; R c is 0 to 1 R f C replaced with 1~6 Alkyl, C 3~6 cycloalkyl, or 0 to 3 R f (CH 2 ) r - is phenyl; R d is hydrogen, F, Cl, Br, OCF 3 , C.F. 3 ,CN,NO 2 ,-OR e ,-(CH 2 ) r C(O)R c ,-NR e R e ,-NR e C(O)OR c ,C 1~6 Alkyl, or 0 to 3 Rf (CH 2 ) r - is phenyl; R e is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, and 0 to 3 R f (CH 2 ) r - selected from phenyl; R f is hydrogen, halo, NH 2 , OH, or O(C 1~6 alkyl); p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; As defined and described in WO 2013 / 106641 and US 2015 / 0018344, each of which is incorporated herein by reference in its entirety.

[0183] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and thereby the formula I-vv-1 or I-vv-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: R 1 teeth, (a) 0 to 4 R 1a C replaced with 2~3 hydroxyalkyl, where R 1a are independently F, Cl, -OH, -CHF 2 , -CN, -CF 3 ,-OCH 3 , and cyclopropyl; (b) -O(C 1~3 alkyl) and 0 to 4 R 1a C replaced with 1~3 alkyl, where R 1a are independently F, Cl, -OH, -CHF 2 , -CN, -CF 3 , and cyclopropyl; (c) 0 to 7 R 1a C replaced with 4~8 alkyl, where R 1a are independently F, Cl, -OH, -CHF 2 ,-CF 3 ,-CN-OCH 3 , cyclopropyl, and -OP(O)(OH) 2 selected from; (d) -(CH 2 ) 2~4 NHC(O)(C 1~6 alkyl), -(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1~6 alkyl), -(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0~1 NH(C 1~6 alkyl) or -(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0~1 N(C 1~4 alkyl) 2 ; (e) -OH, -OCH 3 ,C 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)NH 2 , -C(O)NH(C 1~3 alkyl), -C(O)NH(C 1~6 hydroxyalkyl), -C(O)NH(C 3~6 cycloalkyl), -C(O)NH(C 3~6 Fluorocycloalkyl), -NHC(O)(C 1~3 alkyl), -NHC(O)O(C 1~3 alkyl), -NHS(O) 2 CH 3 , -S(O) 2 N.H. 2 , -S(O) 2 (C 1~3 alkyl), -S(C 1~3 alkyl), thiazolyl, methylpyrazolyl, and C substituted with -OH and cyclopropyl 1~3 cyclohexyl substituted with 0 to 2 substituents independently selected from alkyl; (f) -(CH 2 ) 2 (phenyl), and this phenyl is -C(O)NH 2 , -C(O)NH(C 1~3 alkyl) or -S(O) 2 N.H. 2 replaced with; or (g) -C(O)(C 1~3 piperidinyl substituted with alkyl; And; R 2 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, or triazolyl, each of which is F, Cl, -OH, -CN, C 1~3 Alkyl, -CH 2 C(O)OCH 3 , -O(C 1~3 alkyl), -NH 2 , -NH(C 1~3 alkyl), -NH(cyclopropyl), -C(O)NH 2 , -NHC(O)(C 1~3 alkyl), -NH(tetrahydropyranyl), hydroxypyrrolidinyl, =O, -O(piperidinyl), and pyridinyl; and R 3 teeth, (a) F, -OH, -CH 3 ,-CF 3 , and C 3~6 C substituted with 0 to 4 substituents independently selected from cycloalkyl 1~6 Alkyl; (b) F, -OH, C 1~3 Hydroxyalkyl, -CH 3 ,-CF 2 H, -NH 2 , and -C(O)OCH 2 CH 3 C substituted with 0 to 2 substituents independently selected from 3~6 cycloalkyl; (c) oxetanyl, tetrahydropyranyl, or fluorotetrahydropyranyl; (d) -OH, -CN, -O(C 1~3 alkyl), C 1~3 Hydroxyalkyl, -C(O)NH 2 , -S(O) 2 N.H. 2 ,-NHS(O) 2 (C 1~3 phenyl substituted with 0 to 2 substituents independently selected from alkyl), pyrazolyl, imidazolyl, and methyltetrazolyl; or (e) [ka] And; As defined and described in WO 2014 / 074675 and US 2015 / 0284382, each of which is incorporated herein by reference in its entirety.

[0184] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-xx-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: R 1 is an optionally substituted aromatic heterocyclic group or an optionally substituted C 6~14 is an aryl group; R 2 is a hydrogen atom or a substituent; R 3 and R 4 are independently a hydrogen atom or a substituent, or R 3 and R 4 taken together to form an optionally substituted ring; R 5 and R 6 are independently a hydrogen atom or a substituent, or R 5 and R 6 taken together to form an optionally substituted ring; X is CR 7 R 8 ,NR 9 , O or S; R 7 and R 8are independently a hydrogen atom or a substituent, or R 7 and R 8 are taken together to form an optionally substituted ring; and R 9 is a hydrogen atom or a substituent; As defined and described in WO 2015 / 068856 and US 2015 / 0133451, each of which is incorporated herein by reference in its entirety.

[0185] In certain embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (IAP) binding moiety. [ka] and this gives the formula I-yy-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and variable R is Ohoka, N. et al. (2017). In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein, each of which is incorporated herein by reference in its entirety. (IAP)-dependent Protein Erasers (SNIPERs). Journal of Biological Chemistry, 292(11), 4556-4570.

[0186] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-zz-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: R 1 represents non-existence, A or Q-Het, Z is [ka] and here X represents O, S or N, Y represents C or N, T represents C or N, or Z represents a pyridine group or a pyridazine group, R a is absent or OR 3 , C.F. 3 , Hal, or NO 2 and R b is absent, A, or COHet, and R 2 represents H, Het, Q-Het, Cyc, A or OA; Each Het is independently a 4- to 9-membered monocyclic ring, or a fused, spiro, or bridged bicyclic ring, which ring is saturated, unsaturated, or aromatic, and the ring is 1 to 3 heteroatoms independently selected from N, O, and S, and the groups CO, SO or SO 2 , where one or two H atoms are A, OA, COA, CN, Hal, NO 2 ,OR 3 , SOA and / or SO 2 can be replaced by A, Cyc is the group SO, SO 2 , or CO as required, and CO(NR 3 ) 2 , COHet, OR 3 ,Het 1 ,A,CH 2 het 1 , N.H. 2 ,NHCOA,OCH 2 Cyc 1 , S.O. 2 represents a 4-8 saturated carbocyclic ring, optionally substituted once or twice by a group selected from A and -SA(=NH)(=O), Each Q is independently a straight or branched alkylene having 1 to 6 carbon atoms, where 1 to 5 H atoms are OR 3 , Hal, and N(R 3 ) 2 and 1 or 2 CH 2 The groups are CO, SO, SO 2 and N.R. 3 or Q is saturated, unsaturated or aromatic and contains 1 to 3 heteroatoms independently selected from N, O and S. represents a 4- to 8-membered divalent heterocyclic ring, including Each A is independently a straight or branched alkyl having 1 to 10 carbon atoms, where 1 to 7 H atoms are -OR 3 ,Hal,NHSO 2 A.S.O. 2 A, SOA, and N(R 3 ) 2 and 1, 2 or 3 non-adjacent -CH 2 - group is -CO-, NR 3 may be replaced by groups independently selected from and -O-; Each Hal is independently F, Cl, Br or I; Each R 3 are independently H or C 1 ~C 6 -alkyl, where one H atom is OH, O-C 1 ~C 6 -alkyl, and Hal, Each Het 1 is independently a 5- or 6-membered saturated monocyclic heterocycle containing 1 to 3 N atoms and / or O atoms, optionally monosubstituted by A, Cyc 1 represents cycloalkyl having 3 to 7 atoms; as defined and described in WO 2014 / 008992 and US 2015 / 0141396, each of which is incorporated herein by reference in its entirety .

[0187] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-aaa-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is a monocyclic heteroaryl; R 1 is 1 to 3 R 10 a monocyclic or bicyclic heteroaryl optionally substituted with; R 2 is -C(O)NH 2 , -C(O)NH-R 0 , -C(O)NH-R 00 -OH, -C(O)NH-R 00 -OR 0 , -C(O)N(R 0 ) 2 , -C(O)NH-cycloalkyl, -C(O)NH-heterocycloalkyl, -C(O)NH-(R 0 optionally substituted pyrazolyl), -C(O)-R 0 , -C(O)-cycloalkyl, -S(O) 2 N.H. 2 , -S(O) 2 NH-R 0 , -S(O) 2 NH-cycloalkyl, -R 00 -OH, -R 00 -OR 0 ,-R 00 -(morpholin-4-yl)phenyl, oxadiazolyl, or tetrazolyl, and R 0 and where R 2 The oxadiazolyl in R 0 ,R 00 -OH or R 0 -OR 0 may be replaced with; R 3 is, H, R 0 , halogen, lower alkyl or haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, -C(O)N(R 0 ) 2 ,-R 00 -cycloalkyl, -R 00 -heterocycloalkyl, -R 00 -phenyl, -R 00 -OH or -R 00 -OR 0 , where R 3 cycloalkyl, heterocycloalkyl, phenyl and pyridyl, R 0, halogen, -C(O)OR 0 , -C(O)-R 0 , -OH, -OR 0 , -S(O) 2 -R 0 , -O-lower alkyl or haloalkyl, -OR 00 -(morpholin-4-yl), -R 00 -OH, -R 00 -OR 0 , morpholin-4-yl, or -R 00 -(morpholine-4-yl) may be substituted; R 10 may be the same or different from each other, R 0 , halogen, lower alkyl or haloalkyl, cycloalkyl, -OR 0 , optionally substituted amino, -O-lower alkyl or haloalkyl, -R 00 -OH, -R 00 -OR 0 or -R 00 - is optionally substituted with amino, R 0 are the same or different from each other and are lower alkyl; R 00 are the same or different from each other and are lower alkylene; As defined and described in WO 2011 / 043371, which is incorporated herein by reference in its entirety.

[0188] In some embodiments, the compound of formula I-aaa-1 has the formula I-aaa-2, I-aaa-3, or I-aaa-4: [ka] [ka] or a pharmaceutically acceptable salt thereof, where: LBM, L, R 1 ,R 2 ,R 3 , and R 10 each of is as defined above.

[0189] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-bbb-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is selected from O, S, and NH; A is selected from aryl or heteroaryl; R is independently at each occurrence hydrogen, cyano, halo, hydroxy, -N0 2 ,-NR 3 R 4 , optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl selected; wherein the optional substituents are independently at each occurrence halo, alkyl, haloalkyl, cyano, -NR 5 R 6 or -COOR 7 selected from; R 1 is independently selected at each occurrence from hydrogen, halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and arylalkyl may be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo; Y is a direct bond, O, -C(O)- or NR 7 selected from; R 2 independently at each occurrence are hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl, -S0 2 R 5 or selected from oxo; R 3 and R 4 is independently selected from hydrogen, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; Substituents are independently at each occurrence halo, haloalkyl or -COOR 7 selected from; R 5 and R 6 are independently hydrogen, alkyl, COR 7 or -COOR 7 selected from; R 7 is independently selected at each occurrence from hydrogen or alkyl; and m, n and p are selected from 1, 2 or 3; As defined and described in WO 2013 / 042137, which is incorporated herein by reference in its entirety.

[0190] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-ccc-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring Z 1 is an optionally substituted heteroaryl; Ring Z 2 is an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl or a direct bond; R 1 is alkyl, cyano, -NR a R b or an optionally substituted group, wherein the optionally substituted group is selected from cycloalkyl, aryl or heterocyclyl; where the substituent is independently at each occurrence alkyl, alkoxy , halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH 2 -O-alkyl, -OP(O)(O-alkyl) 2 or -CH 2 -OP(O)(O-alkyl) 2 And; R 2 is an optionally substituted group independently at each occurrence selected from alkyl or cycloalkyl; where the substituent is independently at each occurrence halogen, alkoxy, hydroxyl, hydroxyalkyl , haloalkyl or haloalkoxy; R 3 independently at each occurrence are hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR a R b , hydroxyl or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO 2 -alkyl or optionally substituted cycloalkyl; m and n are independently 1 or 2; As defined and described in WO 2015 / 104662 and US 2016 / 0326151, each of which is incorporated herein by reference in its entirety.

[0191] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-ddd-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X 1 and X 3 are independently CH or N; 2 is CR 2 or N; but X 1 ,X 2 or X 3 Only one of them is N; A is O or S; Y is -CH 2 - or O; Ring Z is aryl or heterocyclyl; R 1is, independently at each occurrence, halo or optionally substituted heterocyclyl; where the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NR a R b And; R 2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NR a R b ; where the substituent is alkyl, amino, halo or hydroxyl; R 3 is alkyl or hydroxyl at each occurrence; R a and R b are independently hydrogen, alkyl, acyl or heterocyclyl; m and n are independently 0, 1 or 2; p is 0 or 1; As defined and described in WO 2015 / 104688 and US 2016 / 0340366, each of which is incorporated herein by reference in its entirety.

[0192] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and this gives the formula I-eee-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Z 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or is absent; Z 2 is optionally substituted cycloalkyl, aryl or heterocyclyl; R 1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted is substituted arylalkyl or optionally substituted heterocyclylalkyl; R 2 represents, at each occurrence, hydrogen, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; R 3 represents, at each occurrence, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NR a R b And; R a and R b independently for each occurrence are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; m is 0, 1 or 2 in each occurrence; and n is 0, 1, or 2 in each occurrence; As defined and described in WO 2015 / 193846 and US 2017 / 0152263, each of which is incorporated herein by reference in its entirety.

[0193] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-fff-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and R 0 is hydrogen or C 1 ~C 4 -represents alkyl, where this C 1 ~C 4 - the alkyl radical may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of hydroxy and halogen; R 1 is hydrogen, halogen, cyano, C(=O)OH, C(=O)OR a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b ,C(=O)R d , hydroxy or C 1 ~C 6 -represents alkyl, where this C 1 ~C 6 -Alkyl radicals include hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -alkyl, NH 2 , N.H.R. a , N(R a )R b , C optionally mono- or polysubstituted by the same or different radicals from the group consisting of halogens 1 ~C 6 -C optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy, halogen 3 ~C 8 -cycloalkoxy, R c optionally mono- or polysubstituted by the same or different radicals from the group consisting of heterocycloalkyl, optionally mono- or polysubstituted by the same or different radicals from the group consisting of; Or C 1 ~C 6 -represents alkoxy, where this C 1 ~C 6 -Alkoxy radicals include hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -alkyl, NH 2 , N.H.R. a , N(R a )R b , C optionally mono- or polysubstituted by the same or different radicals from the group consisting of halogens 3 ~C 8 -cycloalkyl, C optionally mono- or polysubstituted by the same or different radicals from the group consisting of halogens 1 ~C 6 -C optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy, halogen 3 ~C 8 -cycloalkoxy, R c heterocycloalkyl optionally mono- or polysubstituted by the same or different radicals from the group consisting of R c aryl optionally mono- or polysubstituted by the same or different radicals from the group consisting of R c optionally mono- or polysubstituted by the same or different radicals from the group consisting of 5- or 6-membered heteroaryls optionally mono- or polysubstituted by the same or different radicals from the group consisting of , Or C 3 ~C 8 -represents cycloalkoxy or heterocycloalkoxy, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, or aryloxy or 5- or 6-membered heteroaryloxy, where alkoxy and 5- or 6-membered heteroaryloxy are hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,C 1 ~C 6 -Alkyl and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy, Or C 3 ~C 8 -represents cycloalkyl or heterocycloalkyl, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, Or C 2 ~C 6 -alkenyl or C 2 ~C 6 -represents alkynyl or Or aryl, 5- to 10-membered heteroaryl, aryl-C 1 ~C 4 -Alkyl or 5- or 6-membered heteroaryl-C 1 ~C 4 -represents alkyl, where aryl and heteroaryl are halogen, hydroxy, cyano, C(=O)OH, C(=O)OR a ,C 1 ~C 6 -Alkyl, C 3 ~C 8 -cycloalkyl and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy; R a is C 1 ~C 6 -Alkyl, C 3 ~C 10 -represents cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are halogen, hydroxy, cyano, C 1 ~C 3 -Alkyl, C 1 ~C 3 -alkoxy, heterocycloalkyl, -C(=O)O-C 1 ~C 6 -Alkyl and S(=O) 2 -C 1 ~C 6 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkyl; R b is C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl; Or R a and R b together with the nitrogen atom form a 5- or 6-membered heterocycle, which includes hydroxy, halogen, cyano, and C 1 ~C 6 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkyl; R c is hydroxy, halogen, cyano, C 1 ~C 3 -alkyl or C 1 ~C 3 -represents alkoxy; R d is hydrogen, C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl; R 2 is hydrogen, C 1 ~C 6 -alkyl or C 3 ~C 6 -represents cycloalkyl; R 13 is hydrogen or C 1 ~C 6 -represents alkyl; W contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, and R 3 and the same or different radicals R 4 represents a 5-membered heteroaryl, which may be mono- or polysubstituted as necessary, or W is R 3 and the same or different radicals R 4 represents pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl 1,3,5-triazinyl, which may be mono- or polysubstituted as necessary; R 3 is hydrogen, halogen, cyano, C(=O)R a , N.H. 2 , N.H.R. a , N(R a )R b , N(H)C(=O)R a or C 1 ~C 6 -represents alkyl; Here C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)R a , C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -alkyl, NH 2 , N.H.R. a , N(R a )R b ,C 1 ~C 6 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of -cycloalkoxy, Here C 1 ~C 6 -Alkoxy and C 3 ~C 8 - the cycloalkoxy can optionally be mono- or polysubstituted by the same or different halogen radicals; Or C 1 ~C 6 -Alkyl is C 3 ~C 6 - optionally mono- or polysubstituted by the same or radicals from the group consisting of cycloalkyl and heterocycloalkyl, Here C 3 ~C 6 -Cycloalkyl and heterocycloalkyl are halogen, cyano, C 1 ~C 3 -Alkyl and C 1 ~C 3 - can be optionally mono-, di- or tri-substituted by the same or different radicals from the group consisting of alkoxy, Or C 1 ~C 6 -alkyl is optionally mono- or polysubstituted by the same or different radicals from the group consisting of aryl and 5- or 6-membered heteroaryl, Here, aryl and 5- or 6-membered heteroaryl are halogen, cyano, C 1 ~C 3 -Alkyl and C 1 ~C 3 - can be optionally mono-, di- or tri-substituted by the same or different radicals from the group consisting of alkoxy, Or R 3 is C 1 ~C 6 -represents alkoxy; Here C 1 ~C 6 -Alkoxy is hydroxy, halogen, cyano, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 3 ~C 8 -cycloalkyl, C 1 ~C 4 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkoxy, Or C 3 ~C 6 -cycloalkyl, heterocycloalkyl or C 5 ~C 11 -represents spirocycloalkyl, where cycloalkyl, heterocycloalkyl and spirocycloalkyl are hydroxy, halogen, cyano, C(=O)R a , C(=O)OH, C(=O)OR a ,C 1 ~C 6 -Alkyl and C 1 ~C 4 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy; Or represents an aryl or a 5- to 10-membered heteroaryl, where aryl and heteroaryl are halogen, hydroxy, cyano, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, NO 2 , N.H. 2 , N.H.R. a , N(R a )R b , N(H)C(=O)R a ,C 3 ~C 8 -cycloalkyl, C 1 ~C 3 -Alkoxy and C 1 ~C 3 -alkyl, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of C 1 ~C 3 -alkyl can optionally be mono- or polysubstituted by the same or different halogen radicals; R 4 is halogen, hydroxy, cyano or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl, halogen, C 1 ~C 6 -alkoxy, C 2 ~C 6 -alkenyl, C 2 ~C6 -alkynyl, C 3 ~C 10 -cycloalkyl, may be optionally mono- or polysubstituted by the same or different radicals from the group consisting of 3- to 10-membered heterocycloalkyl and aryl, where C 1 ~C 6 -Alkoxy can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of halogen, wherein aryl can be optionally mono- or polysubstituted by the same or different radicals R. ; Or R 4 represents aryl or heteroaryl, which may optionally be mono- or polysubstituted by the same or different radicals R; Or R 4 is C(=O)R a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b ,C(=O)OR a , N.H. 2 , N.H.R. a , N(R a )R b , N(H)C(=O)R a , N(R a )C(=O)R a , N(H)C(=O)NH 2 , N(H)C(=O)NHR a , N(H)C(=O)N(R a )R b , N(R a )C(=O)NH 2 , N(R a )C(=O)NHR a , N(R a )C(=O)N(R a )R b , N(H)C(=O)OR a , N(R a )C(=O)OR a , NO 2 , N(H)S(=O)R a , N(R a )S(=O)R a , N(H)S(=O) 2 R a , N(R a )S(=O) 2 R a , N=S(=O)(R a )R b ,OC(=O)R a ,OC(=O)NH 2 ,OC(=O)NHR a ,OC(=O)N(R a )R b , SH, S.R. a , S(=O)R a ,S(=O) 2 R a ,S(=O) 2 N.H. 2 ,S(=O) 2 NHR a ,S(=O) 2 N(R a )R b or S(=O)(=N-R a )R b represents; R is halogen, cyano, C 1 ~C 6 -Alkyl, C 2 ~C 6 -alkenyl, C 2 ~C 6 -alkynyl, C 3 ~C 10 -Cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, C(=O)R a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b ,C(=O)OR a , N.H. 2 , N.H.R. a , N(R a )R b , N(H)C(=O)R a , N(R a )C(=O)R a , N(H)C(=O)NH 2 , N(H)C(=O)NHR a , N(H)C(=O)N(R a )R b , N(R a )C(=O)NH 2 , N(R a )C(=O)NHR a , N(R a )C(=O)N(R a )R b , N(H)C(=O)OR a , N(R a )C(=O)OR a , NO 2 , N(H)S(=O)R a , N(R a )S(=O)R a , N(H)S(=O) 2 R a , N(R a )S(=O) 2 R a , N=S(=O)(R a )R b ,OH,C 1 ~C 6 -Alkoxy, OC(=O)R a ,OC(=O)NH 2 ,OC(=O)NHR a ,OC(=O)N(R a )R b , SH, S.R. a , S(=O)R a ,S(=O) 2 R a ,S(=O) 2 N.H. 2 ,S(=O) 2 NHR a ,S(=O) 2 N(R a )R b or S(=O)(=NR a )R b represents; n represents 0 or 1; Y is: [ka] represents a group selected from, where * represents the point of attachment of this group to the rest of the molecule; R 5 is hydrogen, C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -Alkoxy and C 3 ~C 8 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl; R 6 is hydrogen or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C 3 ~C 10 -cycloalkyl, C(=O)R a , C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -Alkoxy and C 3 ~C 8 -cycloalkoxy, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of -cycloalkoxy or C 3 ~C 10 -represents cycloalkyl, where C 3 ~C 10 -Cycloalkyl is hydroxy, halogen, cyano and C 1 ~C 6 -alkyl, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of C 1 ~C 6 -alkyl can be optionally substituted by hydroxy or represents heterocycloalkyl, where Heterocycloalkyl is halogen, cyano, C 1 ~C 3 -Alkyl and C 1 ~C 3 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy, or represents an aryl or a 5- or 6-membered heteroaryl, where Aryl and 5- or 6-membered heteroaryl include halogen, cyano, C 1 ~C 3 -Alkyl, C 1 ~C 3 -Alkoxy, S(=O) 2 N.H. 2 ,S(=O) 2 NHR a and S(=O) 2 N(R a )R bmay optionally be mono- or polysubstituted by the same or different radicals from the group consisting of; R 7a is hydrogen, halogen, N(R a )R b ,C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; R 7b is hydrogen, halogen or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; Or R 7a and R 7b together with the carbon atom, C 3 ~C 6 - forms a cycloalkyl, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, Or R 7a and R 7b together represent an oxo group; R 7c is hydrogen, halogen, N(R a )R b ,C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; R 7d is hydrogen, halogen or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; Or R 7c and R 7d together with the carbon atom, C 3 ~C 6 - forms a cycloalkyl, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, Or R 7c and R 7d together represent an oxo group; R 8a is hydrogen, halogen, N(R a )R b ,C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; R 8b is hydrogen, halogen or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; Or R 8a and R 8b together with the carbon atom, C 3 ~C 6 - forms a cycloalkyl, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, R 8c is hydrogen, halogen, N(R a )R b ,C 1 ~C 6 -alkyl or C 3 ~C 10 -represents cycloalkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; R 8d is hydrogen, halogen or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -alkoxy, C 3 ~C 8 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkyl and heterocycloalkyl; Or R 8c and R 8d together with the carbon atom, C 3 ~C 6 - forms a cycloalkyl, which includes hydroxy, halogen, cyano and C 1 ~C 6 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkyl, Or R 8c and R 8d together represent an oxo group; o represents 0, 1 or 2; p represents 0, 1 or 2; q represents 0, 1 or 2; r represents 0, 1 or 2; s represents 0, 1 or 2; Here, o, p, q, r and s do not represent 0 at the same time; Z is C(=O), CR 9 R 10 ,NR 11 , O, S, S(=O) and S(=O) 2 represents a group selected from; R 9 is hydrogen or C 1 ~C 6 -represents alkyl R 10 is hydrogen, halogen, cyano, C(=O)R a , C(=O)OH, C(=O)OR a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b , N(H)C(=O)R a , N(R b )C(=O)R a ,S(=O) 2 R a , hydroxy, N(R a )R b and C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)R a , C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 1 ~C 4 -Alkoxy and C 3 ~C 8 -cycloalkoxy, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of -cycloalkoxy or C 1 ~C 6 -represents alkoxy, where C 1 ~C 6 -Alkoxy means hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 3 ~C 8 -cycloalkyl, C 1 ~C 4 -alkoxy, C 3 ~C 8 - may be optionally mono- or polysubstituted by the same or different radicals from the group consisting of cycloalkoxy, heterocycloalkyl, aryl and 5- or 6-membered heteroaryl, where Aryl and 5- or 6-membered heteroaryl include halogen, cyano, C 1 ~C 3 -Alkyl and C 1 ~C 3 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy or represents aryloxy or 5- or 6-membered heteroaryloxy, where aryloxy and 5- or 6-membered Heteroaryloxy is hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a ,C 1 ~C 3 -Alkyl and C 1 ~C 3 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy, Or C 3 ~C 8 -cycloalkyl, C 3 ~C 8 -cycloalkyl-C 1 ~C 4 -alkyl, heterocycloalkyl or heterocycloalkyl-C 1 ~C 4 - represents alkyl, which can be hydroxy, halogen, cyano, C(=O)R a , C(=O)OH, C(=O)OR a ,C 1 ~C 6 -Alkyl and C 1 ~C 6 -alkoxy, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of C 1 ~C 6 - the alkoxy can optionally be mono- or polysubstituted by the same or different halogen radicals or oxo groups; Or C 2 ~C 6 -alkenyl or C 2 ~C 6 -represents alkynyl or Or aryl, 5- to 10-membered heteroaryl, aryl-C 1 ~C 4 -Alkyl or 5- or 6-membered heteroaryl-C 1 ~C 4 -represents alkyl, where Aryl and heteroaryl are halogen, hydroxy, cyano, C(=O)OH, C(=O)OR a , N.H.R. a , N(R a )R b ,C 1 ~C 3 -Alkyl, C 3 ~C 8 -cycloalkyl and C 1 ~C 3 - can be optionally mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy; Or R 9 and R 10 together with the carbon atom, C 3 ~C 8 - forms a cycloalkyl or 4- to 6-membered heterocycle, where This C 3 ~C 8 -Cycloalkyl radical or this 4- to 6-membered heterocycle is hydroxy, halogen, cyano, C 1 ~C 6 -Alkyl, C(=O)R a may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of and oxo groups; R 11 is hydrogen, C(=O)R a ,C(=O)OR a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b ,S(=O) 2 R a ,S(=O) 2 N(R a )R b or C 1 ~C 6 -represents alkyl, where C 1 ~C 6 -Alkyl is hydroxy, halogen, cyano, C(=O)R a ,C(=O)OR a ,C(=O)NH 2 ,C(=O)N(H)R a , C(=O)N(R a )R b ,S(=O) 2 -C 1 ~C 6 -Alkyl, N(R a )R b ,C 3 ~C 8 -cycloalkyl, C 1 ~C 4 -Alkoxy and C 3 ~C 8 -cycloalkoxy, which may optionally be mono- or polysubstituted by the same or different radicals from the group consisting of C 3 ~C 8 -cycloalkyl, C 1 ~C 4 -Alkoxy and C 3 ~C 8 - the cycloalkoxy can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of hydroxy and halogen; Or C 3 ~C 8 -cycloalkyl, heterocycloalkyl or heterocycloalkyl-C 1 ~C 4 -represents alkyl, which can be hydroxy, halogen, cyano, C 1 ~C 6 -Alkyl, C 1 ~C 6 -alkoxy, wherein alkyl and alkoxy are optionally monosubstituted or polysubstituted by the same or different radicals from the group consisting of halogen and oxo groups. may be substituted or polysubstituted; Or C 2 ~C 6 -alkenyl or C 2 ~C 6 -represents alkynyl or Or aryl, 5- to 10-membered heteroaryl, aryl-C 1 ~C 4 -Alkyl or 5- or 6-membered heteroaryl-C 1 ~C 4 -represents alkyl, where Aryl and heteroaryl are halogen, hydroxy, cyano, C(=O)OH, C(=O)OR a ,C 1 ~C 3 -Alkyl, C 3 ~C 8 -cycloalkyl and C 1 ~C 3 - can optionally be mono- or polysubstituted by the same or different radicals from the group consisting of alkoxy; As defined and described in WO 2015 / 091426 and US 2016 / 0311833, each of which is incorporated herein by reference in its entirety.

[0194] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-ggg-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is phenylene or a 5- to 6-membered heteroarylene containing 1 to 3 heteroatoms selected from O, S, and N, where Ring A is optionally further substituted. optionally substituted with lower alkyl, Ring B is phenylene, a 5- to 6-membered heterocycloalkylene containing 1 to 3 heteroatoms selected from O, S, and N, or 1 to 3 members selected from O, S, and N a 5- to 6-membered heteroarylene containing 5- to 6-membered heteroatoms, where ring B is optionally substituted with an optionally further substituted lower alkyl; R 3 is hydrogen, lower alkyl optionally substituted with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl selected from where phenyl, heterocycloalkyl, and heteroaryl are optionally substituted with one or two groups independently selected from lower alkyl, and alkoxy is optionally substituted with tri(alkyl)silyl. has been replaced according to R 4 is selected from heteroarylene and arylene, each of which is optionally substituted or R 4 and R 3 together with the nitrogen to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R 4 is an alkylene chain having from 1 to 3 carbon atoms optionally substituted with one or two groups independently selected from lower alkyl and cycloalkyl, each of these groups is optionally substituted with hydroxyl or alkoxy, or R 4 does not exist, R 5 is C(O)NR 51 ,NR 52 , and O or R 5 does not exist, but R 4 does not exist, then R 5 does not exist, R 6 is an alkylene chain or an alkenylene chain having one or two double bonds, Here, the alkylene chain or alkenylene chain has 2 to 10 carbon atoms, wherein the alkylene or alkenylene chain is optionally substituted with one or two groups independently selected from lower alkyl and cycloalkyl, each of these groups being hydroxyl or alkoxy. replaced as necessary, and Furthermore, one or two of the carbon atoms in this alkylene chain can be O, S, SO, SO 2 , or NR 61 has been replaced as necessary by and Here, two of the carbon atoms of this alkylene chain are optionally connected by an alkylene chain of two or three carbon atoms to form a 5- to 7-membered ring. R 7 is NR 71 and O or R 7 does not exist, R 51 is selected from hydrogen and lower alkyl, R 52 is hydrogen, lower alkyl, and -C(O)OR 81 selected from R 61 is hydrogen, lower alkyl, and -C(O)OR 81 selected from R 71 is hydrogen, lower alkyl, and -C(O)OR 81 selected from, and R 81 is lower alkyl; As defined and described in WO 2014 / 143672 and US 2016 / 0002265, each of which is incorporated herein by reference in its entirety.

[0195] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-hhh-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and HET is 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; where this heteroaryl is R a and R b is replaced with; 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), -C(O)NH 2 ,-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 And; R 1 teeth, (I C 1~6 Alkyl, 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 1~6 Fluoroalkenyl)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 1~4alkylenyl)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 -CH 2 CF=(tetrahydropyranyl), where R x is C 3~6 Cycloalkyl, tetrazolyl, 1,1-dioxidetetrahydrothiophenyl, 1,1-dioxidethiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl , and triazinyl, where each cyclic group is F, -OH, -CH 3 , -C(CH 2 ) 2 OH, -OCH 3 , -C(O)CH 2 CN, -S(O) 2 CH 3 , -S(O) 2 N.H. 2 , -NHC(O)CH 3 , -N(S(O) 2 CH 3 ) 2 ,-CH 2 CH 2 (acetamidophenyl), -CH 2 CH 2 (methoxyphenyl), -CH 2 CH 2 substituted with 0 to 3 substituents independently selected from (sulfamoylphenyl), oxetanyl, benzyl, 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 alkyl), -NHS(O) 2 (C 1~3 alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl; (iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each of which represents -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) 2 NH(C 1~4 alkyl), -NH(C 1~3 alkyl), -N(C 1~3 alkyl) 2 , -O(C 1~3 alkylenyl)N(C 1~3 alkyl) 2 ,-CH 2 (morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl, methylsulfonylazetidinyl, and -C(O)(methylsulfonylazetidinyl) ); or (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 -Zion is; and R 2 teeth, (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)NH 2 , -(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)(C 1~4 fluoroalkyl); (ii) -(C 1~4 alkylenyl)R y and here R y is C 3~6 cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each of which is 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 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)NH 2 , -C(O)NH(C 1~3 alkyl), -C(O)(difluorophenyl), -NH 2 , -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 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 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)NH 2 , -C(O)NH(C 1~3 alkyl), -NHC(O)(C 1~3 alkyl), -NHC(O)S(O) 2 (C 1~3 alkyl), -S(O) 2 N.H.2 , -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 what is being done And; As defined and described in WO 2015 / 103453 and US 2015 / 0191464, each of which is incorporated herein by reference in its entirety.

[0196] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, formula I-iii-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. is, and [ka] is a single or double bond; W is CH, CH-CH, O, S, NR 6 , and CO; Y is N or CR 9 And; Z is N or C, and W is CH and Y is CR 9 , then Z is N; R 4 is hydrogen, halogen, OR 6 ,CN,NR 7 R 8 ,C.H. 2 OR 6 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic ring, optionally substituted carbocycle, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 haloalkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 Alkynyl, CO 2 R 6 , S.O. 3 R 6 , S.O. 2 R 6 and S.O. 2 NR 7 R 8 selected from; R 5 is hydrogen, halogen, OR 6 , C replaced as necessary 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 haloalkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 1 ~C 6 haloheteroalkyl, optionally substituted C 1 ~C 6 alkenyl, and optionally substituted C 1 ~C 6 selected from alkynyl; or R 4 and R 5 are joined to form an optionally substituted non-aromatic ring; Each R 6 are each independently an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted non-substituted aryl optionally fused to a substituted aryl or substituted heteroaryl. Aromatic ring, hydrogen, optionally substituted C 1 ~C 10 Alkyl, optionally substituted C 1 ~C 10 haloalkyl, and optionally substituted C 1 ~C 10 selected from heteroalkyl; R 7 and R 8 each is independently an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaryl, each optionally fused to a substituted aryl or substituted heteroaryl. Non-aromatic ring, hydrogen, optionally substituted C 1 ~C 10 Alkyl, optionally substituted C 1 ~C 10 haloalkyl, optionally substituted C 1 ~C 10 alkenyl, optionally substituted C 1 ~C 10 alkynyl, and optionally substituted C 1 ~C 10 selected from heteroalkyl or R 7 and R 8 are joined to form an optionally substituted non-aromatic ring; R 9 is hydrogen, halogen, OR 6 ,CN,NR 7 R 8 ,C.H. 2 OR 6 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic ring, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 haloalkyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 Alkynyl, CO 2 R 6 , S.O. 3 R 6 , and SO 2 NR 7 R 8 selected from; A is an optionally substituted aryl or optionally substituted heteroaryl group; Each optionally substituted group is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic, hydroxy, alkoxy, aryloxy , mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, One or more groups independently selected from C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups. is either replaced with; As defined and described in WO 2012 / 068546 and US 2014 / 0155379, each of which is incorporated herein by reference in its entirety.

[0197] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-jjj-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Q represents Ar or Het; E is -(CH 2 ) m CO-, -(CH 2 ) m S.O. 2 ,-(CH 2 ) q -,-(CH 2 ) m NHCO-, or represents a single bond; R 1 is H, OH, NH-C 1 ~C 6 -alkyl, OC 1 ~C 6 -Alkyl, C 1 ~C 6 -Alkyl, C 2 ~C 6 -alkenyl, C 2 ~C 6 -Alkynyl, Cyc, Hal, Het 1 , O-Het 1 , CO-Het 1 ,NH-Het 1 , CO-Ar 1 ,O-Ar 1 , Ar 1 ,NH-Ar 1 ,-(CH 2 ) q het 1 , -CONH-(CH2 ) q het 1 ,-CONH-Het 1 ,-(CH 2 ) q O-Het 1 ,-(CH 2 ) q O-Ar 1 ,-(CH 2 ) q Ar 1 , -CONH-(CH 2 ) q Ar 1 ,-CONH-Ar 1 ,-CONHC 3 ~C 6 -cycloalkyl, -(CH 2 ) q Hal, -(CH 2 ) q Cyc, C.F. 3 ,-(CH 2 ) s NH-(CH 2 ) q -Het 1 ,-(CH 2 ) s NH-(CH 2 ) q -Ar 1 , where NH-C 1 ~C 6 -alkyl, OC 1 ~C 6 -Alkyl, C 1 ~C 6 -Alkyl, C 2 ~C 6 -alkenyl, C 2 ~C 6 -alkynyl, C 3 ~C 6 -cycloalkyl, OC 1 ~C 3 -Alkyl, OH, CONH 2 , N.H. 2 may be substituted with 1 to 3 groups independently selected from; R 2 H, C 1 ~C 6 -Alkyl, C 2 ~C 6 -alkenyl, C 2 ~C 6 -Alkynyl, Hal, CF 3 , preferably H; R 3 Het 1 , Ar 1 ,NR a R b , COOH, -(CH 2 ) q het 1 ,-(CH 2 ) q Ar 1 ,-(CH 2 ) q NR a R b ,-(CH 2 ) q COOH, or C 1 ~C 6 -represents alkyl, where 1 to 3 hydrogen atoms are independently OH or CF 3 can be replaced by; R 4 H, C 1 ~C 6 -Alkyl, C 2 ~C 6 - represents alkenyl, Hal; R a is H, linear, branched or cyclic C 1 ~C 6 -represents alkyl; R b H, Het b , Ar b ,-CO-Het b , -CO-Ar b ,C 3 ~C 8 - cycloalkyl or straight-chain or branched alkyl having 1 to 6 carbon atoms, where 1 to 3 hydrogen atoms are Het b , Ar b , N.H. 2 , N(C 1 ~C 6 -alkyl) 2 ,NH(C 1 ~C 6 -alkyl), N(C 1 ~C 6 -alkyl)(C 3 ~C 8 -cycloalkyl), NH(C 3 ~C 8 -cycloalkyl), O(C 1 ~C 6 -alkyl), CN, OH, CF 3 , can be replaced by Hal; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; q is 1, 2, or 3; s is 0, 1, 2 or 3; Hal represents Cl, Br, I, F, preferably Cl or F; Ar has 6 to 14 carbon atoms, Hal, C 1 ~C 6 -alkyl, -(CH 2 ) m O.C. 1 ~C 6 -Alkyl, CN, OH, NO 2 , C.F. 3 ,-(CH 2 ) m COOH, -(CH 2 ) m COOC 1 ~C 6 - Represents a divalent monocyclic or fused bicyclic arylene group that can be further substituted with 1 to 4 substituents selected from alkyl; Het has 1 to 5 heteroatoms and / or groups -C=O independently selected from N, O, S, Hal, C 1 ~C 6 -alkyl, -(CH 2 ) m O.C. 1 ~C 6 -Alkyl, CN, OH, NO 2 , C.F. 3 ,-(CH 2 ) m COOH, -(CH 2 ) m COOC 1 ~C 6 - represents a divalent monocyclic or fused bicyclic unsaturated, saturated or aromatic heterocyclic group which may be further substituted with 1 to 4 substituents selected from alkyl; Ar 1 has 6 to 14 carbon atoms and is unsubstituted or Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, straight or branched C 1 ~C 6 -alkyl, cycloalkyl, -OH, -OC 1 ~C 6 -alkyl, -COC 1 ~C 6 -alkyl, -NH 2 , -COH, -COOH, -CONH 2 ,-CH 2 O(C 1 ~C 6 -alkyl), etc. b ,-SO 2 NR a R b or SO 2 (C 1 ~C 6 represents a monocyclic or bicyclic aromatic carbocyclic ring which is mono-, di- or trisubstituted by (alkyl); het 1 has 1 to 4 heteroatoms and / or CO groups independently selected from N, O, S and is unsubstituted or Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, straight or branched C 1 ~C 6 -Alkyl, C 3 ~C 8 -cycloalkyl, -OH, -OC 1 ~C 6 -alkyl, -NH 2 , -N(C 1 ~C 6 -alkyl) 2 , -COH, -COOH, -CONH 2 ,-COC 1 ~C 6 -Alkyl, -NHCO(C 3 ~C 6 cycloalkyl), group R b -SO 2 NR a R b or SO 2 (C 1 ~C 6 represents a monocyclic or bicyclic (fused, bridged or spiro) saturated, unsaturated or aromatic heterocyclic ring which is mono-, di- or tri-substituted by (alkyl); het b has 1 to 4 heteroatoms and / or CO groups independently selected from N, O, S and is unsubstituted or Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, -OH, -OC 1 ~C 6 -alkyl, -NH 2 , -COH, -COOH, -CONH2 , or 1 to 3 hydrogen atoms are NH 2 Straight-chain or branched C that can be replaced by 1 ~C 6 -Alkyl, N(C 1 ~C 6 -alkyl) 2 ,NH(C 1 ~C 6 -alkyl), N(C 1 ~C 6 -alkyl)(C 3 ~C 8 -cycloalkyl), NH(C 3 ~C 8 -cycloalkyl), O(C 1 ~C 6 -alkyl), CN, OH, CF 3 ,Hal,C. 3 ~C 8 - Monocyclic or bicyclic (fused or represents a saturated, unsaturated or aromatic heterocyclic ring (spiro); Ar b has 6 to 14 carbon atoms and is unsubstituted or Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, -OH, -OC 1 ~C 6 -alkyl, -NH 2 , -COH, -COOH, -CONH 2 , or 1 to 3 hydrogen atoms are NH 2 Straight-chain or branched C that can be replaced by 1 ~C 6 -Alkyl, N(C 1 ~C 6 -alkyl) 2 ,NH(C 1 ~C 6 -alkyl), N(C 1 ~C 6 -alkyl)(C 3 ~C 8 -cycloalkyl), NH(C 3 ~C 8 -cycloalkyl), O(C 1 ~C 6 -alkyl), CN, OH, CF 3 ,Hal,C. 3 ~C 8 - monocyclic or bicyclic aromatic mono-, di- or tri-substituted by cycloalkyl or a 4- to 8-membered heterocyclic ring containing heteroatoms selected from O, S and N represents a carbocyclic ring; Cyc has 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, and 1 to 5 H atoms are Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, Hal, -CF 3 ,-OCF 3 ,-NO 2 , -CN, perfluoroalkyl, straight or branched C 1 ~C 6 -alkyl, cycloalkyl, -OH, -OC 1 ~C 6 -alkyl, -COC 1 ~C 6 -alkyl, -NH 2 , -COH, -COOH, -CONH 2 ,-CH 2 O(C 1 ~C 6 -alkyl), etc. b ,-SO 2 NR a R b or SO 2 (C 1 ~C 6 represents a saturated or partially unsaturated carbocyclic ring replaced by alkyl); or As defined and described in WO 2012 / 084704 and US 2013 / 0274241, each of which is incorporated herein by reference in its entirety.

[0198] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-kkk-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: R 1 is aryl, heteroaryl, heterocyclyl or (C 1~6 alkyl)R 6 , where the aryl, heteroaryl, and heterocyclyl groups are halo, cyano, R 4 ,C 3~8 cycloalkyl, C 1~3 aminoalkyl, C 1~3 hydroxyalkyl, OR 4 ,NR 4 R 5 ,NR 4 C.O.R. 6 ,NR 4 S.O. 2 R 6 , S.O. 2 NR 4 R 5 ,CONR 4 R 5 and CONR 4 R 5 optionally substituted with one or two substituents selected from the group consisting of; R 2 is aryl, heteroaryl, C 3~8 Cycloalkyl, heterocyclyl or (C 1~6 alkyl)R 6 and where the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R 4 ,OR 4 , O(C 3~8 cycloalkyl), (C=O)OR 4 , S.O. m R 6 , S.O. m R 4 ,NR 4 R 5 , S.O. 2 NR 4 R 5 and N.R. 4 S.O. 2 R 6 optionally substituted with one or two substituents selected from the group consisting of; R 3 is halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R 4 ,OR 4 ,C 3~8 cycloalkyl, SO m R 6 , S.O. m R 4 NR 4 R 5 or (C=O)NR 4 R 5 ,NR 4 (CO)R 6 , S.O. m NR 4 R 5 and N.R. 4 S.O. 2 R 6 And; R 4 is hydrogen or C 1~6 an alkyl, where the alkyl is optionally substituted with 1 to 3 halo or hydroxyl; R 5 is hydrogen or C 1~6 an alkyl, where the alkyl is optionally substituted with halo or hydroxyl; R 6 is aryl, heteroaryl, C 3~8 cycloalkyl or heterocyclyl; m is an integer from 0 to 2; As defined and described in WO 2012 / 129258 and US 2014 / 0194404, each of which is incorporated herein by reference in its entirety.

[0199] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-lll-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is -N= or -CH=; Y is -NR 2 -,-CH 2 selected from the group consisting of -, -CHR- and -O-, so that if Y is -CHR-, then R and R 3together with the carbon to which they are bonded, form a 4- to 6-membered cycloalkyl ring, cycloalkenyl ring, or heterocyclic ring as necessary, where this 4- to 6-membered cycloalkyl ring, cycloalkenyl ring, or heterocyclic ring is A cycloalkyl ring, cycloalkenyl ring, or heterocyclic ring is a C 1~4 Alkyl, C 3~6 cycloalkyl, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR 8 optionally substituted with 1 to 3 substituents independently selected from the group consisting of; or Y is -NR 2 - if R 2 and R 3 together with the nitrogen to which they are attached optionally form a 4- to 6-membered heterocyclic ring, where this 4- to 6-membered heterocyclic ring is C 1~4 Alkyl, C 3~6 cycloalkyl, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR 8 optionally substituted with 1 to 3 substituents independently selected from the group consisting of; R 1 is hydrogen, C 1~10 Alkyl, C 3~8 Cycloalkyl, aryl, heterocyclyl, halogen, -COOR 7 ,-NHR 7 ,-SR 7 ,-OR 7 ,-SO 2 R 7 ,-COR 7 ,-NHCOR 7 , and -CONHR 7 selected from the group consisting of; where the alkyl, cycloalkyl, aryl and heterocyclyl are C 1~4 Alkyl, C 3~6 Cycloalkyl, CN, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR S optionally substituted with 1 to 3 substituents independently selected from the group consisting of -NHR 8 is -N(C 1~4 alkyl)NH 2 or -N(C 3~6 cycloalkyl)NH 2 has been replaced as necessary; R 2 is hydrogen, C 1~10 alkyl, and C 3~8 selected from the group consisting of cycloalkyl; R 3 is hydrogen, C 1~10 Alkyl, C 3~8 Cycloalkyl, aryl, heterocyclyl, and -COOR 7 selected from the group consisting of; where the alkyl, cycloalkyl, aryl and heterocyclyl are C 1~4 Alkyl, C 3~6 cycloalkyl, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR 8 optionally substituted with 1 to 3 substituents independently selected from the group consisting of; R 6 is C 1~10 Alkyl, C 3~8 Cycloalkyl, aryl, heterocyclyl, -COOR 7 ,-SO 2 R 7 , and -COR 7 selected from the group consisting of; where the alkyl, cycloalkyl, aryl and heterocyclyl are C 1~4 Alkyl, C 3~6 cycloalkyl, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR 8 optionally substituted with 1 to 3 substituents independently selected from the group consisting of; R 7 is hydrogen, C 1~10 Alkyl, C 3~8 selected from the group consisting of cycloalkyl, aryl, and heteroaryl; where the alkyl, cycloalkyl, aryl, and heterocyclyl are C 1~4 Alkyl, C 3~6 cycloalkyl, phenyl, CF 3 , heterocyclyl, halogen, -COOR 8 ,-NHR 8 ,-SR 8 ,-OR 8 ,-SO 2 R 8 ,-COR 8 ,-NHCOR 8 , and -CONHR 8 optionally substituted with 1 to 3 substituents independently selected from the group consisting of; and R 8 is hydrogen, C 1~6 Alkyl and C 3~6 selected from the group consisting of cycloalkyl; As defined and described in WO 2013 / 066729 and US 2014 / 0329799, each of which is incorporated herein by reference in its entirety.

[0200] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-mmm-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is independently CH or N; Y is H or methyl; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; Ring A is R 1 optionally substituted with 1 to 3 substituents independently selected from (C 3 ~C 8 ) cycloalkenyl, aryl or heterocycle; R 1 is:H, oxo, (C=O) a O b (C 1 ~C 10 )alkyl, (C=O) a O b -aryl, (C=O) a O b (C 2 ~C 10 )alkenyl, (C=O) a O b (C 2 ~C 10 )alkynyl, CO 2 H, halo, OH, O b (C 1 ~C 6 )fluoroalkyl, (C=O) a NR 5 R 6 ,CN,(C=O) a O b (C 3 ~C 8 )cycloalkyl, S(O) m NR 5 R 6 , SH, S(O) m -(C 1 ~C 10 )alkyl and (C=O) a O b -heterocyclyl, where the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is R a optionally substituted with one or more substituents selected from; R 2 and R 3 are independently R 1 H, (C=O) optionally substituted with one or more substituents selected from a O b C 1 ~C 10Alkyl, (C=O) a O b Aryl, C 2 ~C 10 alkenyl, C 2 ~C 10 Alkynyl, (C=O) a O b heterocyclyl, CO 2 H,CN,O b C 1 ~C 6 Fluoroalkyl, O a (C=O) b NR 5 R 6 , CHO, (N=O)R 5 R 6 , S(O) m NR 5 R 6 , SH, S(O) m -(C 1 ~C 10 )alkyl, (C=O) a O b C 3 ~C 8 selected from cycloalkyl; or R 2 and R 3 have 3 to 7 members in each ring, together with the nitrogen to which they are attached, and in addition to this nitrogen, 1 or 2 members selected from N, O and S may form a monocyclic or bicyclic heterocycle optionally containing further heteroatoms of R 1 optionally substituted with one or more substituents selected from; R 4 are independently, (C 1 ~C 6 )alkyl, OH, methoxy, CF 3 and F, where the alkyl is optionally substituted with OH; R 5 and R 6 are independently H, (C=O) a O b (C 1 ~C 10 )alkyl, (C=O) a O b -aryl, (C=O) a O b (C 2 ~C 10 )alkenyl, (C=O) a O b (C 2 ~C 10 )alkynyl, CO 2 H, O b (C 1 ~C 6 )fluoroalkyl, (C=O) a N(R a ) 2 ,CN,(C=O) a O b (C 3 ~C 8 )cycloalkyl, S(O) m N(R a ) 2 , SH, S(O) m -(C 1 ~C 10 )alkyl and (C=O) a O b -heterocyclyl, where the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is R a optionally substituted with one or more substituents selected from; R a are independently R b ,OH,(C 1 ~C 6 )Alkoxy, halogen, cyclopropyl, CO 2 H,CN,O a (C=O) b (C 1 ~C 6 )alkyl, oxo, and N(R b ) 2 selected from; and R b are independently H and (C 1 ~C 6 ) alkyl; As defined and described in WO 2014 / 058685 and US 2015 / 0299224, each of which is incorporated herein by reference in its entirety.

[0201] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and this gives the formula I-nnn-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is CH or N; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; Ring A is R 1 optionally substituted with 1 to 3 substituents independently selected from (C 3 ~C 8 )cycloalkyl, (C 3 ~C 8 ) cycloalkenyl, aryl or heterocycle; R 1 is H, oxo, (C=O) a O b (C 1 ~C 10 )alkyl, (C=O) a O b -aryl, (C=O) a O b (C 2 ~C 10 )alkenyl, (C=O) a O b (C 2 ~C 10 )alkynyl, CO 2 H, halo, OH, O b (C 1 ~C 6 )fluoroalkyl, (C=O) a NR 5 R 6 ,CN,(C=O) a O b (C 3 ~C 8 )cycloalkyl, S(O) m NR 5 R 6 , SH, S(O) m -(C 1 ~C 10 )alkyl and (C=O) a O b -heterocyclyl, where the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is R a optionally substituted with one or more substituents selected from; R 2 and R 3 are independently R 1 H, (C=O) optionally substituted with one or more substituents selected from a O b C 1 ~C 10 Alkyl, (C=O) a O b Aryl, C 2 ~C 10 alkenyl, C 2 ~C 10 Alkynyl, (C=O) a O b heterocyclyl, CO 2 H,CN,O b C 1 ~C 6 Fluoroalkyl, O a (C=O) b NR 5 R 6 , CHO, (N=O)R 5 R 6 , S(O) m NR 5 R 6 , SH, S(O) m -(C 1 ~C 10 )alkyl, (C=O) a O b C 3 ~C 8 selected from cycloalkyl; or R 2 and R 3 have 3 to 7 members in each ring, together with the nitrogen to which they are attached, and in addition to this nitrogen, 1 or 2 members selected from N, O and S may form a monocyclic or bicyclic heterocycle optionally containing further heteroatoms of R 1 optionally substituted with one or more substituents selected from; R 4 is R a (C 1 ~C 6 )alkyl and (C 3 ~C 6 ) cycloalkyl; R 5 and R 6 are independently H, oxo, (C=O) a O b (C 1 ~C 10 )alkyl, (C=O) a O b -aryl, (C=O) a O b (C 2 ~C 10)alkenyl, (C=O) a O b (C 2 ~C 10 )alkynyl, CO 2 H, O b (C 1 ~C 6 )fluoroalkyl, (C=O) a N(R a ) 2 ,CN,(C=O) a O b (C 3 ~C 8 )cycloalkyl, S(O) m N(R a ) 2 , SH, S(O) m -(C 1 ~C 10 )alkyl and (C=O) a O b -heterocyclyl, where the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are R a optionally substituted with one or more substituents selected from; R a are independently R b ,OH,(C 1 ~C 6 )Alkoxy, halogen, cyclopropyl, CO 2 H,CN,O a (C=O) b (C 1 ~C 6 )alkyl, oxo, and N(R b ) 2 selected from; and R b are independently H and (C 1 ~C 6 ) alkyl; As defined and described in WO 2014 / 058691 and US 2015 / 0274708, each of which is incorporated herein by reference in its entirety.

[0202] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , which gives the formula I-nnn’-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. , and the variable R 3 ,R 4 , X, and Ring A are each as defined and described in WO 2014 / 058691, each of which is incorporated herein by reference in its entirety.

[0203] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-ooo-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are defined above and as practiced herein. As stated in the form, and: Z is the base [ka] represents; where X is CH or N; Y is CH or N; Ra, Rc, and R1 each independently represent H, Hal, or A1; Rb is H or alkyl; Al is a chain or straight-chain alkyl with 1 to 12 C atoms, where 1 or more, for example 1 to 7 H atoms are Hal, ORb, COORb, CN or N(Rb) 2 and 1 or more, preferably 1 to 5 CH 2 Groups are O, CO, NRb or S, SO, SO 2 , 1,2-, 1,3- or 1,4-phenylene, -CH=CH- or -C≡C-; and Hal represents F, Cl, Br, I; As defined and described in WO 2014 / 121931 and US 2015 / 0376167, each of which is incorporated herein by reference in its entirety.

[0204] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-ppp-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Each of R1 and R3 is independently H, (CH 2 ) p CON(R5) 2 ,OA,Hal,COOH,COOA,(CH 2 ) p NHCOA, (CH 2 ) p Het1, (CH 2 ) p Represents NR2R5, or OH; R2 represents H or straight-chain or branched alkyl with 1, 2 or 3 C atoms, where 1 or 2 H atoms of this alkyl group are OR6, NR5R6, Replaced as necessary by NHCOR5, CONR5R6; R4 represents H or A; R5 represents H or straight-chain or branched alkyl with 1, 2 or 3 C atoms; R6 represents H or straight-chain or branched alkyl with 1, 2 or 3 C atoms; Z is absent or represents Ar-diyl or Het-diyl; L is (CH 2 ) n represents 1 or 2 CH 2 The groups are optionally replaced by O and / or CH═CH- groups and / or one or two H atoms are optionally replaced by OR2, NR2R5 or Het1; Ar-diyl, Hal, CN, -CF 3 ,-OCF 3 ,OH,O-A,SO 2 -A, COOH, COOA, -CO-A, O-phenyl, SO 2 -Phenyl, SO 2 -CF 3 , represents 1,2-, 1,3- or 1,4-phenylene, optionally substituted with 1 to 5 groups independently selected from the group consisting of , Het2 and A; Het-diyl represents an unsaturated, saturated or aromatic 5- or 6-membered heterocycle containing 1 to 2 N, O and / or S atoms, which is optionally unsubstituted. Is there or Hal, CN, -CF 3 ,-OCF 3 , O-A, S.O. 2 -A, COOH, COOA, -CO-A, O-phenyl, SO 2 -Phenyl, SO 2 -CF 3 , mono-, di- or tri-substituted by Het2 and / or A; A represents unbranched or branched alkyl containing 1 to 10 C atoms, where 1 to 5 H atoms are optionally replaced by F, and / or here 1 or 2 non-adjacent CHs 2 The groups are optionally replaced by O; Het1 represents morpholinyl, piperidinyl or pyrrolidinyl; Het2 represents morpholinyl, piperidinyl or pyrrolidinyl; Hal represents F, Cl, Br, I; n represents 1, 2, 3, 4, 5 or 6; p represents 0, 1 or 2; As defined and described in WO 2014 / 121942 and US 2015 / 0376206, each of which is incorporated herein by reference in its entirety.

[0205] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-qqq-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring or 4 having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring with ~7 members; n is 0 to 4; Each R 1 are independently -R, halogen, -CN, -NO 2 , -OR, -CH 2 OR, -SR, -N(R) 2 ,-SO 2 R, -SO 2 N(R) 2 , -SOR, -C(O)R, -CO I R, -C(O)N(R) 2 , -C(O)N(R)-OR, -NRC(O)R, -NRC(O)N(R) 2 , Cy, or -NRSO 2 R; or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. fused, spirofused, or bridged bicyclic rings; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, aryl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; R z -R, -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -OR, or -SO 2 N(R) 2 And; Ring B is an unsubstituted 4- to 8-membered partially unsaturated carbocyclic fused ring; and L is C 1~6 a divalent hydrocarbon chain, where one or two methylene units of this chain are independently -NR-, -N(R)C(O)-, -C(O)N(R) -, -N(R)SO 2 -,-SO 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - has been replaced as appropriate by; As defined and described in WO 2012 / 097013 and US 2012 / 0283238, each of which is incorporated herein by reference in its entirety.

[0206] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-rrr-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; n is 0 to 4; Each R 1 are independently -R, halogen, -CN, -NO 2 , -OR, -CH 2 OR, -SR, -N(R) 2 ,-SO 2 R, -SO 2 N(R) 2 , -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R) 2 , Cy, or -NRSO 2 R; or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. fused, spirofused, or bridged bicyclic rings; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Ring B is a cyclopent or cyclohexo fused ring; m is 1~2; p is 0~2; W is N; R z R,CN,NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R)C(O)OR, -NRC(O)N(R) 2 , -OR, or -SO 2 N(R) 2 And; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where one or two methylene units of this chain are independently -NR-, -N(R)C(O)-, -C(O)N(R) -, -N(R)SO 2 -,-SO 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - has been replaced as appropriate by; Each L 2 are independently covalent or C 1~6 a divalent hydrocarbon chain, where one or two methylene units of this chain are independently -NR-, -N(R)C(O)-, -C(O)N(R) -, -N(R)SO 2 -,-SO 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - has been replaced as appropriate by; Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 ,-SO 2 R, -SO 2 N(R) 2 , -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 ,-NRSO 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from: 2-L 2 (R 4 ) p -R 4The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. fused, spirofused, or bridged bicyclic rings; As defined and described in WO 2013 / 106535 and US 2013 / 0231328, each of which is incorporated herein by reference in its entirety.

[0207] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-sss-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring or 4 having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring with ~7 members; n is 0 to 4; Each R 1 are independently -R, halogen, -CN, -NO 2 , -OR, -CH 2 OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -C(O)N(R)-OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms therebetween, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. to form a fused, spirofused, or bridged bicyclic ring; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Ring B is selected from benzo-fused rings and 5- to 6-membered heteroaromatic fused rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B may be optionally substituted with one or more oxo, thioxo, or imino groups; m is 0~4; p is 0~2; W is N or -C(R 3 )-and; R z R,CN,NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -N(R)C(O)OR, -N(R)C(O)N(R) 2 , -OR, or -S(O) 2 N(R) 2 And; R 3 is hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 haloaliphatic, -OR, -C(O)R, or -C(O)N(R) 2 And; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; Each L 2 are independently covalent or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; and Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from; or 2-L 2 (R 4 ) p -R 4 The group is an optionally substituted 4- to 7-membered group having, together with the atoms therebetween, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a fused or bridged bicyclic ring; As defined and described in WO 2014 / 011902 and US 2014 / 0018343, each of which is incorporated herein by reference in its entirety.

[0208] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-ttt-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring or 4 having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring with ~7 members; n is 0 to 4; Each R 1 are independently -R, halogen, -CN, -NO 2 , -OR, -CH 2 OR, -SR, -N(R) 2 , -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, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from one of; 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms therebetween, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. to form a fused, spirofused, or bridged bicyclic ring; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Ring B is a 4- to 8-membered partially unsaturated carbocyclic condensed ring and a 4- to 7-membered partially unsaturated hetero atom having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur. selected from cyclic fused rings; wherein ring B may be optionally substituted with one or more oxo, thiono, or imino groups; m is 0~4; p is 0~2; R z -R, -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -N(R)C(O)OR, -N(R)C(O)N(R) 2 , -OR, or -S(O) 2 N(R) 2 And; R 3 is hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 haloaliphatic, -OR, -C(O)R, or -C(O)N(R) 2 And; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; Each L 2 are independently covalent or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; and Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from; or 2-L 2 (R 4 ) p -R 4 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a fused, spirofused or bridged bicyclic ring; As defined and described in WO 2014 / 011906 and US 2014 / 0018357, each of which is incorporated herein by reference in its entirety.

[0209] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-uuu-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; n is 0 to 4; Each R 1 are independently -R, halogen, -CN, -NO 2 , -OR, -CH 2 OR, -SR, -N(R) 2 , -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, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms therebetween, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. to form a fused, spirofused, or bridged bicyclic ring; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; R x and R y Each of is independently -R, halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , or -N(R)S(O) 2 R or: R x and R y together with the atoms between them, there are m entities [ka] forming a ring B substituted with; Ring B is a benzo-fused ring, a 4- to 8-membered partially unsaturated carbocyclic fused ring, a 4- to 8-membered ring having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 5- to 6-membered heteroaromatic fused ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where this ring B may be optionally substituted by one or more oxo, thiono, or imino groups; m is 0~4; p is 0~2; Q is -O- or -N(R)-, W is N or -C(R 3 )-and; R z -R, -CN, -NO 2 , halogen, -C(O)N(R) 2, -C(O)OR, -C(O)R, -N(R) 2 , -N(R)C(O)OR, -N(R)C(O)N(R) 2 , -OR, or -S(O) 2 N(R) 2 And; R 3 is hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 haloaliphatic, -OR, -C(O)R, or -C(O)N(R) 2 And; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; Each L 2 are independently covalent or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; and Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from; or 2-L 2 (R 4 ) p -R 4 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. members to form a fused, spiro, or bridged bicyclic ring; As defined and described in WO 2014 / 011911 and US 2014 / 0018361, each of which is incorporated herein by reference in its entirety.

[0210] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and this gives the formula I-vvv-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Q is CH, C-CN, or N; X is C-L 2 (R 4 ) p -R x and Y is N; or X is N and Y is C-Rx; Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; R 1 and R 1’ Each of the -R 2 , halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -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, -N(R)C(O)OR, -N(R)C(O)N(R) 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. fused, spirofused, or bridged bicyclic rings; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 10-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a saturated or partially unsaturated heterocyclic ring; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 is independently C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from; Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 N(R) 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from; R x is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -NH[Ar], -OR, or -S(O) 2 N(R) 2 And; R z is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)N(R) 2 , -C(O)OR, -C(O)R, -N(R) 2 , -NH[Ar], -OR, or -S(O) 2 N(R) 2 And; [Ar] is R for m examples 1’ is a phenyl or heteroaromatic ring substituted by; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; L 2 is a covalent bond or C 1~6a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; m is 0~4; n is 0~4; and p is 0~2; As defined and described in WO 2015 / 048281 and US 2015 / 0094305, each of which is incorporated herein by reference in its entirety.

[0211] In some embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and, thereby, the formula I-vvv’-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in the embodiments herein; A, B, C, D, E, F, G, H, X 1 ,X 2 , and X 3 each is independently a carbon, nitrogen, oxygen, or sulfur atom; and R 1 ,R 2 ,R 3 , and R 4 each is independently hydrogen or a substituted group, and the substituted group is C 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur. selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from: R 1 and R 2 , and R 3 and R 4 is a 4- to 7-membered compound having 0 to 3 heteroatoms, each optionally together with atoms between them, independently selected from nitrogen, oxygen, and sulfur. to form a saturated, partially unsaturated, or heteroaryl ring.

[0212] Such IRAK4 inhibitors are well known to those skilled in the art and are described in Scott et al., J.Med.Chem., 2017, 60(24):10071-10091 and Degorce et al., Bioorg.Med.Chem. ,2018,26(4):913-924.

[0213] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] [ka] [ka] , which gives the formulas I-vvv'-2, I-vvv'-3, I-vvv'-4, I-vvv'-5, I-vvv'-6, I-vvv'-7, I -vvv'-8, I-vvv'-9, I-vvv'-10, I-vvv'-11, I-vvv'-12, I-vvv'-13, I-vvv'-14, I- vvv'-15, I-vvv'-16, I-vvv'-17, I-vvv'-18, I-vvv'-19, I-vvv'-20, I-vvv'-21, I-vvv '-22, I-vvv'-23, I-vvv'-24, I-vvv'-25, I-vvv'-26, I-vvv'-27, I-vvv'-28, I-vvv' -29, I-vvv'-30, I-vvv'-31, I-vvv'-32, I-vvv'-33, I-vvv'-34, I-vvv'-35, I-vvv'- 36, I-vvv'-37, I-vvv'-38, and I-vvv'-39: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in the embodiments herein; X 1 ,X 2 , and X 3 each is independently a carbon, nitrogen, oxygen, or sulfur atom; and R 1 ,R 2 ,R 3 , and R 4 each is independently hydrogen or a substituted group, and the substituted group is C 1~6 4- to 7-membered saturated or partially unsaturated heterocyclics having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur. selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from: R 1 and R 2 , or R 3 and R 4 is a 4- to 7-membered saturated 4- to 7-membered heteroatom having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally together with the atoms between them, Forms a partially unsaturated or heteroaryl ring.

[0214] In certain embodiments, the invention provides that IRAK is an inhibitor of IRAK1 and / or IRAK4 [ka] and; thereby, the formula I-www-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: Q is =N- or =CH-; Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclic ring; Each R 1 is independently -R 2 , halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)NR 2 , Cy, or -N(R)S(O) 2 R; or R 1 is the following formula: [ka] selected from one of; Or 2 R 1 The group is an optionally substituted 4- to 7-membered group having, together with the atoms between them, 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. fused, spirofused, or bridged bicyclic rings; Each Cy is independently a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 4-membered carbocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from 10-membered saturated or partially unsaturated heterocyclic rings; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is 1~6aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, contain, in addition to this nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 is independently C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from; R 5 and R 6 each independently hydrogen or -L 2 (R 4 ) p -R x is; or R 5 and R 6 is a 4- to 7-membered partially unsaturated or aromatic compound having 0 to 3 heteroatoms, taken together with atoms between them, independently selected from nitrogen, oxygen, and sulfur. form a ring; Each R 4 are independently halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -N(R)C(O)R, -N(R)C(O)NR 2 , -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group, where the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from; R x is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)NR 2 , -C(O)OR, -C(O)R, -NR 2 , -NH[Ar], -OR, or -S(O) 2 NR 2 And; R z is hydrogen, -R 2 , -CN, -NO 2 , halogen, -C(O)NR 2 , -C(O)OR, -C(O)R, -NR 2 , -NH[Ar], -OR, or -S(O) 2 NR 2 And; [Ar] is an optionally substituted phenyl or an optionally substituted 5- to 6-membered member having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is a heteroaryl ring; L 1 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; L 2 is a covalent bond or C 1~6 a divalent hydrocarbon chain, where the one or two methylene units of this chain are independently -N(R)-, -N(R)C(O)-, -C(O)N (R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 - has been replaced as appropriate by; m is 0~4; n is 0~4; and p is 0~2; As defined and described in WO 2015 / 164374 and US 2015 / 0329498, each of which is incorporated herein by reference in its entirety.

[0215] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] and; thereby, the formula I-xxx-1 [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X and X’ are each independently CR 8 ,N or -N + -O - and; Y is independently, N, -N + -O - or CR 8’ where at least one of X, X’ or Y is N or -N + -O - , and one or less of X, X' or Y is -N + -O - And; R 1 is C 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl;C 2 ~C 6 Alkynyl;-(CR 3a R 3b ) m -(3- to 7-membered cycloalkyl); -(CR 3a R 3b ) m -(3- to 7-membered heterocycloalkyl); -(CR 3a R 3b ) m -(5- to 10-membered heteroaryl); or -(CR 3a R 3b ) m -C 6 ~C 12 aryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl represents 1 to 5 halogens, deuterium, -OR 5 ,-SR 5 ,-NR 11a R 11b , Cyano, C. 1 ~C 6 Alkyl, C 3 ~C 6 cycloalkyl or -C 1 ~C 6 optionally substituted with alkoxy; R 2 is -(CR 3a R 3b ) m -(3- to 10-membered cycloalkyl); -(CR 3a R 3b ) m -(3- to 10-membered heterocycloalkyl); -(CR 3a R 3b ) m -(5- to 10-membered heteroaryl); or -(CR 3a R 3b ) m -C 6 ~C 12 aryl; where the cycloalkyl, heterocycloalkyl, heteroaryl or aryl has 1 to 5 R 4 and when the heteroatom of the heterocycloalkyl and heteroaryl is N, the N is 4’ or R 2 is C 1 ~C 6 alkyl, where this alkyl is NH 2 , optionally substituted with OH or cyano; R 3a and R 3b is hydrogen or C, independently for each occurrence 1 ~C 3 is alkyl; R 4 is independently for each entity: bond, deuterium halogen, cyano, C 1 ~C 6 Alkyl, C 2 ~C 6 alkenyl, oxo, -OR 5 ,-SR 5 , -S(O)R 9 , -S(O) 2 R 9 ,-NR 11a R11b , -C(O)R 10 ,-(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl), -(CR 3a R 3b ) n -(4- to 10-membered heterocycloalkyl) having 1 to 3 heteroatoms, -(CR 3a R 3b ) n -(5- to 10-membered heteroaryl) having 1 to 3 heteroatoms, or -(CR 3a R 3b ) n -C 6 ~C 12 aryl, where the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each independently one to five deuterium, halogen, OR 5 ,-SR 5 ,-NR 11a R 11b , Cyano, C. 1 ~C 6 Alkyl, C 3 ~C 6 cycloalkyl or -C 1 ~C 6 optionally substituted with alkoxy; or two R 4 together with the respective carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is 1 ~3 halogens, deuterium, -OR 5 ,-SR 5 ,-NR 11a R 11b , cyano or C 1 ~C 6 alkyl or C 1 ~C 6 optionally substituted with alkoxy, where the alkyl or alkoxy is halogen, deuterium, -OR 5 ,-SR 5 ,-NR 11a R 11b , or cyano; and if the heteroatom of this heterocycloalkyl is N, then this N is R 4’ has been replaced as necessary; R 4’ is independently C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, -C(O)R 10 , -S(O) 2 R 9 ,-(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl), -(CR 3a R 3b ) n -(4- to 10-membered heterocycloalkyl) or C(O)(CH 2 ) t CN; where the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl each independently represents 1 to 5 deuterium, halogen, OH, cyano, or C 1 ~C 6 optionally substituted with alkoxy; or R 4 and R 4’ together with the respective atom to which each of these is attached forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is 1 to 3 halogens, deuterium, -OR 5 ,-SR 5 ,-NR 11a R 11b , Cyano, C. 1 ~C 6 alkyl or C 1 ~C 6 optionally substituted with alkoxy, where the alkyl or alkoxy is halogen, deuterium, -OR 5 ,-SR 5 ,-NR 11a R 11b , or optionally substituted with cyano; R 5 are independently hydrogen or C 1 ~C 6 alkyl, where this alkyl is halogen, deuterium, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylthiolyl, -NR 11a R 11b , Cyano, C. 1 ~C 6 alkyl or C 3 ~C 6 optionally substituted with cycloalkyl; or two R 5 together with the oxygen atom to which they are attached form a 5- or 6-membered heterocycloalkyl; R 6 is -C(O)NHR 7 , CO 2 R 7 or cyano; R 7 is hydrogen or C 1 ~C 6 is alkyl; Each R 8 are independently hydrogen, halogen, cyano, -OR 5 ,-SR 5 ,-NR 11a R 11b ,C 6 Alkyl, C 3 ~C 6 cycloalkyl, 3- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl or aryl, where the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl has 1 to 3 members Halogen, -NR 11a R 11b ,OR 5 ,-SR 5 , Cyano, C. 1 ~C 3 Alkyl, -C(O)R 10 or optionally substituted with oxo; R 8’ is hydrogen, deuterium, halogen, cyano, -OR 5 ,-SR 5 or NR 11a R 11b And; R 9 is -(CR 3a R 3b ) p -(C 1 ~C 3 alkyl), -(CR 3a R 3b ) p -(4- to 6-membered cycloalkyl), -(CR 3a R 3b ) p -(4- to 6-membered heterocycloalkyl) or -(CR 3a R 3b ) p -(C 5 ~C 9 aryl), where the alkyl, cycloalkyl, heterocycloalkyl or aryl is each fluoro or C 1 ~C 3 optionally substituted with alkyl; R 10 is C 1 ~C 6 alkyl, where this alkyl is deuterium, halogen, OH, C 1 ~C 6 optionally substituted with alkoxy or cyano; R 11a and R 11b are each independently hydrogen or C 1 ~C 6 alkyl, where this alkyl is deuterium, C 1 ~C 6 optionally substituted with alkoxy or cyano; and C 2 ~C 6 If an alkyl, this alkyl is deuterium, C 1 ~C 6 optionally substituted with alkoxy, cyano, halogen or OH; m is independently 0, 1, 2 or 3; n is independently 0, 1, 2 or 3; p is independently 0 or 1; and t is 1, 2 or 3; As defined and described in WO 2015 / 150995 and US 2015 / 0284405, each of which is incorporated herein by reference in its entirety.

[0216] In certain embodiments, the invention provides that IRAK is an IRAK4 inhibitor [ka] , thereby giving the formula I-yyy-1 or I-yyy-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and as described in the embodiments herein. and: X is N or CH; m is 1 or 2; Ar is optionally substituted aryl or optionally substituted heteroaryl; R 1 is hydrogen, C 1~6 Alkyl, C 1~6 alkoxy, hydroxyl, hydroxy-C 1~6 Alkyl, C 1~6 Alkyl-amino, amino-C 1~6 Alkyl, amino-C 1~6 Alkyl-amino, hydroxy-C 1~6 alkylamino, C 3~6 Cycloalkylamino, amino-C 3~6 Cycloalkylamino, amino-C 3~6 Heterocycloalkylamino, aminocarbonyl, halo, hydroxy-C 1~6 alkyl, or hydroxy-C 1~6 is alkoxy; and R 2 is hydrogen or C 1~6 is alkyl; As defined and described in WO 2012 / 007375 and US 2012 / 0015962, each of which is incorporated herein by reference in its entirety.

[0217] As defined above and described herein, IRAK is capable of binding to one or more of IRAK-1, IRAK-2, IRAK-3, or IRAK-4. Possible IRAK binding moiety.

[0218] In some embodiments, IRAK is an IRAK binding moiety capable of binding IRAK-1. In some embodiments, IRAK is an IRAK binding moiety capable of binding IRAK-2. In some embodiments, IRAK is an IRAK binding moiety capable of binding IRAK-3. In some embodiments, IRAK is an IRAK binding moiety capable of binding IRAK-4.

[0219] In some embodiments, IRAK is a moiety described in Aurigene Discovery Tech.Ltd.Presentation:Novel IRAK-4 Inhibitors exhibit highly potent anti-proliferative activity in DLBCL cell lines with activation MYD88 L264P mutation, e.g., AU-5850 , AU-2807, AU-6686, and AU-5792, etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0220] In some embodiments, the IRAK is Scott, J.S. et al.Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88 Diffuse Large B-cell Lymphoma.J.Med. The parts described in Chem.Manuscript,Nov,29 2017,10.1021 / acs.jmedchem.7b01290, for example: [ka] [ka] [ka] [ka] selected from, where [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0221] In some embodiments, the IRAK is Powers, J.P. et al., Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4, Bioorg. Med Chem Lett. (2006) 16(11):2842- 45, for example: [ka] [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0222] In some embodiments, IRAK is Wang, et al., Crystal Structure of IRAK-4 Kinase in Complex with Inhibitors:Serine / Threonine Kinase with Tyrosine as a Gatekeeper,Structure,2006,14(12):1835-44 For example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0223] In some embodiments, the IRAK is Wang, Z. et al., Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associated kinase 4, Bioorg. Med. Chem Lett., 2015, 25( 23):5546-50, for example: [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0224] In some embodiments, the IRAK is Chaudhary, D. et al., Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders, J .Med Chem.,2015,58(1):96-110, for example: [ka] [ka] [ka] [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0225] In some embodiments, IRAK is as described in Zhang, D. et al., Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma, Clin.Can.Res., 2017, 23(7):1748-59 The parts to be included, for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0226] In some embodiments, IRAK is Cushing, L. et al., IRAK4 kinase controls Toll-like receptor induced inflammation through the transcription factor IRF5 in primary human monocytes, J.Bio.Chem., 2017, 292(45) :18689-698, for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0227] In some embodiments, the IRAK is Li,N.et al.,Targeting interleukin-1 receptor-associated kinase for human hepatocellular carcinoma,J.Ex.Clin.Can.Res.,2016,35(1):140 -50, e.g.: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0228] In some embodiments, the IRAK is a compound described in Dudhgaonkar, S. et al., Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity, J. of Immun., 2017, 198(3):1308-19. The parts mentioned, for example: BMS-986126 etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0229] In some embodiments, IRAK is a moiety described in Wang, Z. et al., IRAK-4 Inhibitors for Inflammation, Cur.Top.Med.Chem., 2009, 9(8):724-37; for example: [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0230] In some embodiments, the IRAK is Kelly,P.N.et al.,Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy,J.Exp.Med.,2015,212(13) :2189-201, for example: [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0231] In some embodiments, IRAK is Dunne, A. et al., IRAK1 and IRAK4 Promote Phosphorylation, Ubiquitation, and Degradation of MyD88 Adaptor-like(Mal), J.Bio.Chem., 2010, 285(24) :18276-82, for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0232] In some embodiments, IRAK comprises a moiety described in Kueppers, R., IRAK inhibition to shut down TLR signaling in autoimmunity and MyD88-dependent lymphomas, J. Exp. Med, 2015, 212(13):2184. for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0233] In some embodiments, the IRAK is derived from Chiang, E.Y. et al., Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1 / 4 Kinase Activity across human Cell Types, J. Immunol., 2011,186(2):1279-88, for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0234] In some embodiments, IRAK is Lee, K.L. et al., Discovery of Clinical Candidate 1-{[2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy} -7-methoxyisoquinoine-6-carboxamide(PF-06650833),a Potent,Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 9IRAK4),by Fragment-Based Drug Design,J.Med.Chem.,2017,60(13) :5521-42, for example: [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0235] In some embodiments, the IRAK is an anti-inflammatory agent of Kondo, M. et al., Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5 / 6 nephrectomized rats, Naunyn-Schmiedeberg's Arch Pharmacol. ,2014,387(10):909-19, for example: [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0236] In some embodiments, the IRAK is a derivative of Song, K.W. et al., The Kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells, Mol. Immunol. .,2009,46(7):1458-66, such as: RO0884, RO1679, or RO6245, where: [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0237] In some embodiments, IRAK is Vollmer, S. et al., The mechanism of activation of IRAK1 and IRAK4 by interleukin-1 and Toll-like receptor agonists, Biochem. J., 2017, 474(12):2027 -38, such as: IRAK-IN-1A, JNK-IN-7, and JNK-IN-8, where [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0238] In some embodiments, the IRAK ligand is McElroy, W.T., et al., Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation, Med.Chem.Lett., 2015, 6(6): 677-82, for example: [ka] [ka] [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0239] In some embodiments, the IRAK ligand is Seganish, W.M., et al., Discovery and Structure Enabled Synthesis of 2,6-diaminopyrimidine-4-one IRAK4 Inhibitors,Med.Chem.Lett.,2015,6(8) :942-47, for example: [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0240] In some embodiments, the IRAK ligand is Seganish, W.M., et al., Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4,Bioorg.Med.Chem.Lett.,2015,25(16 ):3203-207, for example: [ka] [ka] [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0241] It is. In some embodiments, the IRAK ligand is McElroy, W.T., et al., Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine Inhibitors of interleukin-1 receptor-associated kinase 4, Bioorg.Med.Chem. Lett.,2015,25(9):1836-41, for example: [ka] [ka] [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0242] In some embodiments, the IRAK ligand is Tumey, L.N., et al., Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4,Bioorg.Med.Chem.Lett.,2014,24(9 ):2066-72, for example: [ka] [ka] [ka] [ka] etc., and here [ka] is bonded to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0243] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the expression I-zzz: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and X, Y, R 1 ,R 2 , and R 3 is as defined and described in WO 2018 / 209012, which is incorporated herein by reference in its entirety.

[0244] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-aaaa: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and R 1 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 , and R 7 as defined and described in US 2018 / 0230157, which is incorporated herein by reference in its entirety.

[0245] In certain embodiments, the invention provides that IRAK is an IRAK1 and / or IRAK4 binding moiety. [ka] And; This gives the formula I-bbbb: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and ring A1, ring B, ring C, L 1A ,R 1 ,R 2 ,R 3 ,R 4 , n, and p are as defined and described in WO 2018 / 098367, which is incorporated herein by reference in its entirety.

[0246] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-cccc: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and R 1 ,R 2 ,R 3 ,R 4 ,R 5 , and R 6 is as defined and described in WO 2018 / 052058, which is incorporated herein by reference in its entirety.

[0247] In certain embodiments, the invention provides that IRAK is an IRAK1 and / or IRAK4 binding moiety. [ka] And; This gives the formula I-dddd: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and ring A, ring B, R 1 ,R 2 , and R 3 as defined and described in US 2017 / 0369476, which is incorporated herein by reference in its entirety.

[0248] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-eeee: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and R 1 ,R 2 ,R 3 , and R 4 is as defined and described in WO 2017 / 207385, which is incorporated herein by reference in its entirety.

[0249] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-ffff: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. , and the rings A, X, Y, L 1 , Cy 1 , Cy 2 ,R 1 ,R 8 ,R 9 , k, m, and n are as defined and described in WO 2017 / 205766, which is incorporated herein by reference in its entirety.

[0250] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the expression I-gggg: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. , and rings A, L 1 , Cy 1 , Cy 2 ,R 1 R 8 ,R 9 , m, and n are as defined and described in WO 2017 / 205762, which is incorporated herein by reference in its entirety.

[0251] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the expression I-hhhh: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. , and the rings A, R 1 ,R 3 ,R 4 ,R 5 , and R 16 as defined and described in WO 2017 / 108723, which is incorporated herein by reference in its entirety.

[0252] In certain embodiments, the invention provides that IRAK is an IRAK1 and / or IRAK4 binding moiety. [ka] And; This gives formula I-iiii: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. , and the rings X, Z, R 1 ,R 2 ,R 3 ,R 4 ,R a and p are as defined and described in WO 2017 / 049068, which is incorporated herein by reference in its entirety.

[0253] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-jjjj: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and X, X', Y, Y', Z, R 1 ,R 2 ,R 3 ,R 4a ,R 4b ,R 5a ,R 5b and R 6 is as defined and described in WO 2017 / 033093, which is incorporated herein by reference in its entirety.

[0254] In certain embodiments, the invention provides that IRAK is an IRAK4 binding moiety. [ka] And; This gives the formula I-kkkk: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in the embodiments herein. and X, X', Y, Y', Z, R 1 ,R 2 ,R 3 ,R 4a ,R 4b ,R 5a ,R 5b and R 6 is as defined and described in WO 2017 / 033093, which is incorporated herein by reference in its entirety.

[0255] In certain embodiments, the invention provides that IRAK is an IRAK-4 binding moiety, whereby the formula I-llll: [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in the embodiments herein. , and the variable R 1 ,R 2 , and R 3 as described and defined in WO 2017 / 148902 and US 2019 / 071432, each of which is incorporated herein by reference in its entirety.

[0256] In certain embodiments, the invention provides that IRAK is an IRAK-4 binding moiety, whereby the formula I-mmmm: [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in the embodiments herein. , and the variable R 1 ,R 2 , and R 3 as described and defined in WO 2017 / 108744, each of which is incorporated herein by reference in its entirety.

[0257] In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is. In some embodiments, IRAK is [ka] It is.

[0258] In some embodiments, IRAK is selected from those illustrated in Table 1 below. Linker (L)

[0259] As defined above and described herein, L is a divalent moiety that attaches IRAK to LBM.

[0260] In some embodiments, L is a divalent moiety that attaches IRAK to LBM.

[0261] In some embodiments, L is a covalent bond or a divalent, saturated or unsaturated, straight or branched C 1~50 is a hydrocarbon chain, where the 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D) 2 -, -CRF-, -CF 2 -, -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- , [ka] has been replaced by, where: Each -Cy- is independently phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocycrylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl, a 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; an optionally substituted divalent ring selected from 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms; and Each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0262] In some embodiments, each -Cy- is independently an optionally substituted divalent 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 carbocycrylenyl. 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 carbocycrylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-membered group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a 7-membered saturated or partially unsaturated heterocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-membered group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is an 11-membered saturated or partially unsaturated spiroheterocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-membered group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 5-membered group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a 6-membered heteroarylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-membered group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. It is a 10-membered bicyclic heteroarylenyl.

[0263] In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is. In some embodiments, -Cy- is [ka] It is.

[0264] In some embodiments, -Cy- is selected from those illustrated in Table 1 below.

[0265] 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. In some embodiments, r is 10.

[0266] In some embodiments, r is selected from those illustrated in Table 1 below.

[0267] In some embodiments, L is -NR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-NR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-NR-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-NR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NR-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-NR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-NR-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-NR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-NR-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NR-Cy-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-NR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NR-Cy-(C 1~10 aliphatic)-.

[0268] In some embodiments, L is -CONR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-CONR-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-CONR-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-CONR-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-CONR-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-CONR-Cy-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-CONR-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-CONR-Cy-(C 1~10 aliphatic)-.

[0269] In some embodiments, L is -NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-NRCO-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NRCO-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-NRCO-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-NRCO-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NRCO-Cy-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-NRCO-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-NRCO-Cy-(C 1~10 aliphatic)-.

[0270] In some embodiments, L is -O-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-O-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-O-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-O-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-O-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-O-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-O-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-O-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-O-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-O-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-O-Cy-. In some embodiments, L is -Cy-(C 1~10aliphatic)-Cy-O-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-O-Cy-(C 1~10 aliphatic)-.

[0271] In some embodiments, L is -Cy-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-. In some embodiments, L is -Cy-(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-Cy-. In some embodiments, L is -(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-Cy-(C 1~10 aliphatic)-.

[0272] In some embodiments, L is -NR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -NR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -NR-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-NR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -NR-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -NR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -Cy-NR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -Cy-(CH 2 ) 1~10 -NR-. In some embodiments, L is -(CH 2 ) 1~10 -Cy-(CH 2 ) 1~10 -NR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -Cy-NR-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -NR-Cy-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -Cy-NR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -NR-Cy-(CH 2 ) 1~10 -is.

[0273] In some embodiments, L is -CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -CONR-(CH 2 CH 2 O) 1~10 CH 2 CH 2 -is. In some embodiments, L is -Cy-CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -CONR-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -Cy-CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -Cy-(CH 2 ) 1~10 -CONR-. In some embodiments, L is -(CH 2 ) 1~10 -Cy-(CH 2 ) 1~10 -CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -Cy-CONR-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -CONR-Cy-. In some embodiments, L is -Cy-(CH 2 ) 1~10 -Cy-CONR-(CH 2 ) 1~10 -is. In some embodiments, L is -Cy-(CH 2 ) 1~10 -CONR-Cy-(CH 2 ) 1~10 -is.

[0274] In some embodiments, L is -NRCO-(CH 2 ) 1~10 -is. In some embodiments, L is -(CH 2 ) 1~10 -NRCO-(CH 2 ) 1~10 -...

Claims

1. Formula I: 【Chemistry 1204】 or a pharma- ceutically acceptable salt thereof, wherein in formula I: X １ and X ２ are independently a covalent bond, -CR ２ -, -O-, -CF ２ --, 【Chemistry 1205】 or X １ and X ２ is -CR=CR-; X ３ and X ４ are independently -CH ２ -, -C(O)-, -C(S)-, or 【Chemistry 1206】 and Ring X and Ring Y are independently fused rings selected from 5-6 membered saturated, partially unsaturated, or heteroaryl rings having, in addition to the nitrogen already depicted in Ring X and Ring Y, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ｘ and R ｙ Each of R is independently hydrogen, deuterium, ｚ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -CF ２ R, -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -C(S)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)S(O) ２ R, -OP(O)R ２ , -OP(O)(OR) ２ , -OP(O)(OR)NR ２ , -OP(O)(NR ２ ) ２ , -Si(OR)R ２ and -SiR ３ Selected from: Each R is independently selected from hydrogen or an optionally substituted group, the optionally substituted group being selected from 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 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; Each R ｚ is independent, 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; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １～５０ A hydrocarbon chain, wherein the 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D) ２ -, -CRF-, -CF ２ -, -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-, 【Chemistry 1207】 has been replaced by: 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- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-membered to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and IRAK is an IRAK binding moiety, A compound or a pharma- ceutically acceptable salt thereof.

2. The compound has the following formula: 【Chemistry 1208】 2. The compound of claim 1, selected from any one of:

3. The IRAK binding portion comprises: 【Chemistry 1209】 3. A compound according to claim 1 or claim 2, which is: Ring A is a 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic 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; Ring C is a phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ２ and L ３ each independently represents a covalent bond, or C １～３ wherein one to three methylene units of the chain are independently selected from -O-, -C(O)-, -C(S)-, -C(R ... ２ -, -CH(R)-, -CF(R)-, -C(F) ２ -, -N(R)-, -S-, -S(O) ２ optionally replaced by - or -CR=CR-; Each R １ are independently hydrogen, deuterium, -R ５ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)(NR)R, -P(O)(OR) ２ , -P(O)(NR ２ ) ２ , -CFR ２ , -CF ２ (R), -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), —C(O)R, —C(O)OR, or —C(O)NR ２ and Each R is independently hydrogen, deuterium, or an optionally substituted group, and the optionally substituted group is selected from the group consisting of 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 atom optionally taken together with the atoms between them form an optionally substituted 4-11 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 ２ are independently hydrogen, deuterium, -R ５ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)(NR)R, -P(O)(OR) ２ , -P(O)(NR ２ ) ２ , -CFR ２ , -CF ２ (R), -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ or -N(R)S(O) ２ R; R ４ teeth, 【Chemistry 1210】 , hydrogen, or an optionally substituted group, the optionally substituted group being selected from C １～６ selected from aliphatic or 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, or spiro rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is a phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, 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; Each R ３ are independently hydrogen, deuterium, -R ５ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)(NR)R, -P(O)(OR) ２ , -P(O)(NR ２ ) ２ , -CFR ２ , -CF ２ (R), -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ or -N(R)S(O) ２ R; Each R ５ is independent, C １～６ an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each n is 0, 1, or 2; each m is 0, 1, 2, 3, or 4; and each p is 0, 1, 2, 3 or 4; The compound, or a pharma- ceutically acceptable salt thereof.

4. The compound has the following formula: 【Chemistry 1211】 【Chemistry 1212】 【Chemistry 1213】 【Chemical 1214】 【Chemistry 1215】 【Chemistry 1216】 【Chemical 1217】 4. The compound of claim 3, which is one of:

5. 4. The compound of claim 3, wherein Ring B is a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

6. The compound according to any one of claims 3 to 5, wherein Ring C is phenyl or a 6- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. the IRAK binding moiety comprising: 【Chemistry 1218】 【Chemical 1219】 3. The compound according to claim 1 or claim 2,

8. L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １～２０ A hydrocarbon chain, wherein the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -NRS(O) ２ -, -S(O) ２ The compound according to any one of claims 1 to 7, which is replaced by NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-.

9. 9. The compound according to any one of claims 1 to 8, wherein the compound is selected from any one of the compounds depicted in Table 1, or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

11. 11. The pharmaceutical composition of claim 10 further comprising an additional therapeutic agent.

12. A pharmaceutical composition for use in a method of degrading IRAK4 protein kinase in a patient or biological sample, comprising a compound according to any one of claims 1 to 9, said method comprising administering said compound or said pharmaceutical composition to said patient or contacting said biological sample with said compound or said pharmaceutical composition.

13. A pharmaceutical composition for treating an IRAK4-mediated disorder, disease, or condition in a patient, comprising a compound according to any one of claims 1 to 9.

14. The composition of claim 13, wherein the composition is administered in combination with an additional therapeutic agent.

15. The composition of claim 13, wherein the disorder, disease or condition mediated by IRAK4 is selected from 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.

16. The composition of claim 13, wherein the IRAK4-mediated disorder, disease or condition is selected from a MyD88-driven disorder.

17. 17. The composition of claim 16, wherein the MyD88-driven disorder is selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

18. 10. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for treating a disorder, disease or condition mediated by IRAK4 in a patient.

19. 20. The use of claim 18, further comprising treating the patient with an additional therapeutic agent.

20. The use of claim 18, wherein the disorder, disease or condition mediated by IRAK4 is selected from 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 use according to claim 18, wherein the IRAK4 mediated disorder, disease or condition is selected from MyD88 driven disorders.

22. 22. The use of claim 21, wherein the MyD88-driven disorder is selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

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