IRAK decomposing agents and their use

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] References to 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 modulating one or more interleukin-1 receptor-related kinases ("IRAKs") by ubiquitination and / or degradation by compounds according to the present invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods for using said compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates major regulator proteins and degrades misfolded or abnormal proteins. UPP is central to numerous cellular processes, and its deficiency or imbalance can lead to the development of various diseases. The covalent binding 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 can be divided into four families: HECT-domain E3, U-box E3, monomeric RING E3, and multi-subunit 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) entitled "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem. 2014, 458, 421-437) Title "RBR E3 ubiquitin ligases: new structures, new insights, new See also "questions." and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347), titled "Roles of F-box proteins in cancer."

[0005] UPPs play a major role in the degradation of short-lived regulatory proteins crucial for various fundamental cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. Their pathways are involved in the pathogenesis of several forms of malignancy, several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral disease, and muscle wasting pathologies. Many diseases are associated with abnormal UPPs, which negatively impact the regulation of the cell cycle and division, cellular responses to stress and extracellular modulators, neural network morphogenesis, cell surface receptors, ion channels, secondary pathways, DNA repair, and organelle biodevelopment.

[0006] Abnormalities in this process have recently been associated with the development of several diseases, both congenital and acquired. These diseases fall into two main groups: (a) diseases resulting from a loss of function that leads to the stabilization of specific proteins, and (b) diseases resulting from the acquisition of function (i.e., abnormal or accelerated degradation of protein targets).

[0007] UPPs are used to induce selective proteolysis and involve the use of fusion proteins to artificially ubiquitize 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 via recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the potential for transient control of protein expression. Such compounds may induce inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents, potentially providing new models for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46). In this field, there is a continuing need for effective treatments 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 (e.g., transcription factors) remain obstacles to the development of effective anticancer drugs. Therefore, small molecule therapeutics that affect E3 ligase-mediated proteolysis and target cancer-related proteins such as interleukin-1 receptor-related kinases ("IRAKs") retain their potential as therapeutic agents. Thus, there remains a need to find bifunctional compounds that are useful IRAK degraders 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 [Overview of the project] [Means for solving the problem]

[0009] Summary of the Invention This application relates to novel bifunctional compounds that function to recruit IRAK kinases to E3 ubiquitin ligases for degradation, as well as methods for their preparation and use. In particular, this disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of IRAK kinases (which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein). The advantage of the compounds provided herein is that they enable a wide range of pharmacological activities that are compatible with the degradation / inhibition of IRAK kinases. Furthermore, this specification provides methods for using effective amounts of the compounds described herein for the treatment or mitigation of disease conditions such as cancer, e.g., multiple myeloma.

[0010] This application further relates to a bifunctional molecule effective for regulating targeted ubiquitination, which includes a bifunctional molecule in which the cerebron-binding portion is bound to a ligand that binds to IRAK kinase. Such a compound has the general formula: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0011] The compounds of the present invention and their pharmaceutically acceptable compositions include a bifunctional molecule in which the cerebron-binding portion is bound to a ligand that binds to IRAK kinase, as shown in the following general formula I: [ka] Alternatively, it has been found that targeting of IRAK kinase degradation can be achieved by using a bifunctional molecule having a pharmaceutically acceptable salt thereof. In general formula I, each variable is as defined and described herein.

[0012] The compounds of the present invention, and their pharmaceutically acceptable compositions, are useful for treating various diseases, disorders, or conditions related to the modulation of signaling pathways involving IRAK kinase. Such diseases, disorders, or conditions are those described herein.

[0013] The compounds provided by the present invention are also useful for studying IRAK enzymes in biological and pathological phenomena; for studying intracellular signaling pathways occurring in body tissues; and for comparative evaluation of novel IRAK inhibitors or IRAK degraders or other regulators in vitro or in vivo at kinase, signaling pathway, and cytokine levels. [Modes for carrying out the invention]

[0014] Detailed description of a specific embodiment 1. General description of specific embodiments of the present invention: The compounds and compositions of the present invention are useful as degradants and / or inhibitors of one or more IRAK protein kinases. In some embodiments, the provided compounds degrade and / or inhibit IRAK-1 / 2 / 3 / 4.

[0015] In a particular embodiment, the present invention relates to formula I: [ka] We provide a compound of or a pharmaceutically acceptable salt thereof, here: X 1 and X 2 These are independently covalent, -CR2-, -O-, -CF2-, [ka] is; or X 1 and X 2 -CR=CR-; X 3 and X 4independently, -CH2-, -C(O)-, -C(S)-, or [Chemical formula] and; ring X and ring Y are each independently a fused ring selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen already shown in rings X and Y; R x and R y each independently is selected from hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3; each R is independently selected from hydrogen or an optionally substituted group, and the optionally substituted group is selected from C 1~6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic 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, or: two R groups on the same carbon or nitrogen optionally combine together with the atoms between them to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to this carbon or nitrogen; each R z is independently C 1~6The groups are selected from substituted groups as needed, including 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2, 3, or 4; L is a covalent or divalent, saturated or unsaturated, linear or branched C 1~50 It is a hydrocarbon chain, where L has 0 to 6 methylene units that are independent of -C(D)(H)-, -C(D)2-, -CRF-, -CF2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, [ka] It has been replaced by, here: Each -Cy- is independently a phenylenyl, an 8- to 10-membered bicyclic aryrenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclilenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclilenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclilenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclilenyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 11-membered saturated or partially unsaturated heterocyclilen having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. A optionally substituted divalent ring selected from a member-saturated or partially unsaturated spiroheterolenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryrenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryrenyl having 1 to 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 the IRAK coupling portion.

[0016] 2. Compounds and Definitions: The compounds of the present invention generally include those described above, and are further illustrated by the classes, subclasses, and species disclosed herein. Where used herein, unless otherwise specified, the following definitions apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table, CAS versions, and Handbook of Chemistry and Physics, 75th edition. Furthermore, general principles of organic chemistry are described in their entirety in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and in "March's Advanced Organic Chemistry," 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire content of which is incorporated herein by reference.

[0017] The terms “aliphatic” or “aliphatic group,” as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing one or more fully saturated or unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”) that is fully saturated or contains one or more unsaturated units but is not aromatic, and has one bond site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains one to six aliphatic carbon atoms. In some embodiments, an aliphatic group contains one to five aliphatic carbon atoms. In other embodiments, an aliphatic group contains one to four aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains one to three aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains one to two aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, is not aromatic, and has one bond site to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, saturated or unsaturated alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

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

[0019] The term "lower alkyl" refers to C 1~4 This refers to linear or branched alkyl groups. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term "lower haloalkyl" refers to a C atom that is substituted with one or more halogen atoms. 1~4 This refers to a linear or branched alkyl group.

[0021] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any quaternary form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR) + This means one or more of the following (including, for example, in N-substituted pyrrolidinyls).

[0022] The term "unsaturated," as used herein, means a portion having one or more unsaturated units.

[0023] As used herein, the term "divalent C 1~8 (or C 1~6 "Saturated or unsaturated, straight or branched hydrocarbon chains" means straight or branched, divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0024] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) 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 by substituents. Suitable substituents include those listed 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 by substituents. Suitable substituents include the substituted aliphatic groups listed below.

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

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

[0028] The term “aryl,” used alone or as part of a larger term such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” means a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, with at least one ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” means an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may have one or more substituents. Where the term “term” is used herein, and within its scope, it refers to a group in which an aromatic ring is condensed with one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl).

[0029] The terms “heteroaryl” and “heteroaryl,” used alone or as part of a larger term (e.g., “heteroarylkyl” or “heteroaralkoxy”), mean a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; 6, 10, or 14 π electrons shared in a cyclic configuration; and 1 to 5 heteroatoms in addition to carbon atoms. The term “heteroatom” means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “hetero-arra-” also, as used herein, encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and whose radical or bond site lies on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a ring that is substituted as necessary. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are substituted independently as necessary.

[0030] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic rings, which are either saturated or partially unsaturated and have one or more, preferably 1 to 4, heteroatoms in addition to the carbon atoms, as defined above. As used in reference to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl), + It may also be NR (as in N-substituted pyrrolidinyl).

[0031] Heterocyclic rings can be bonded to their parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be substituted as needed. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are interchangeable herein and also encompass groups in which the heterocyclyl ring is fused to one or more aryl rings, heteroaryl rings, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl). The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” means an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are substituted independently as needed.

[0032] As used herein, the term “partially unsaturated” means a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated sites, but not to encompass aryl or heteroaryl moies as defined herein.

[0033] As described herein, the compounds of the present invention may include “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a designated moiety are replaced with appropriate substituents. Unless otherwise indicated, an “optionally substituted” group may have appropriate substituents on each of its substituted moieties, and if one or more positions in any given structure can be replaced with one or more substituents selected from a particular group, the substituents may be the same or different at each position. The substituent combinations envisioned by the present invention are preferably combinations that result in the formation of stable compounds or chemically feasible compounds. The term “stable,” as used herein, means a compound that remains substantially unchanged when produced, detected, and, in particular embodiments, subjected to conditions that enable their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] A suitable monovalent substituent on the substitutable carbon atom of the "substituted as needed" group is, independently, a halogen;-(CH2) 0~4 R ○ ;-(CH2) 0~4 Ure ○ ;-O(CH2) 0~4 R ○ -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (This is R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 Ph (This is R ○ It can be substituted with);-CH=CHPh(this is R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 -Pyridyl (This is R ○ Can be replaced by);-NO2;-CN;-N3;-(CH2)0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR-;SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-SC(S)SR ○ 、-(CH2) 0~4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)2NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1~4 is a straight-chain or branched-chain alkylene)O-N(R ○ )2; or -(C 1~4 is a straight-chain or branched-chain alkylene)C(O)O-N(R ○ )2, where each R ○ can be substituted as defined below and, independently, is hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or independently is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or, regardless of the above definition, two independent occurrences of R ○ together with the atom(s) between them independently form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, which can be substituted as defined below.

[0035] R ○ (R○ The appropriate monovalent substituents on the ring formed by the two independent entities of these atoms joining together with the atom between them are halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C 1~4 (Straight-chain or branched alkylene)C(O)OR ● , or -SSR ● And here each R ● It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or selected from 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. ○ Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0036] Suitable divalent substituents on the saturated carbon atoms of the "substituted as needed" groups include: =O, =S, =NNR* 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here's R * Each independent entity is a hydrogen, which can 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. Suitable divalent substituents bonded to the substituted carbon of the vicinal of the "optionally substituted" group include -O(CR * 2) 2~3 O- is mentioned, and here R * Each independent entity is a hydrogen, which can 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.

[0037] R * Suitable substituents on the aliphatic group include halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0038] A suitable substitutionable substituent on the nitrogen of the "substituted as needed" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed; here each R † C can be substituted independently of hydrogen, as defined below. 1~6 Aliphatic, unsubstituted-OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or notwithstanding the above definition, R † Two independent entities of these atoms, together with the atom(s) between them, form an unsubstituted, 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, each containing 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0039] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms, or independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term “Provided Compounds” means any genus, subgenus, and / or species described herein.

[0041] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is appropriate for use in contact with human and lower animal tissues without excessive toxicity, irritation, and allergic reactions, and that is balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by other methods used in the field, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethanesulfonates. Examples include nitrates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates.

[0042] Examples of salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0043] Unless otherwise stated, the structures illustrated herein also mean that all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of that structure, such as the R and S configurations for each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures illustrated herein also mean that all compounds differ only in the presence of one or more isotope-enriched atoms. For example, the structures of the present invention in which hydrogen is replaced by deuterium or tritium, or carbon 13 C or 14 Compounds having the present invention in which C is replaced with enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools according to the present invention, as probes in biological assays, or as therapeutic agents.

[0044] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits IRAK kinase with a measurable affinity. In certain embodiments, the inhibitor is 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 It has and / or coupling constants.

[0045] As used herein, the term “degradant” is defined as a heterobifunctional compound that binds to and / or inhibits both IRAK kinase and E3 ligase with measurable affinity, resulting in ubiquitination and subsequent degradation of IRAK kinase. In certain embodiments, the degradant is a DC with a concentration 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 It has.

[0046] The compounds of the present invention can be anchored 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 bonded to the provided compound via a suitable substituent. In this specification, the term “suitable substituent” means a moiety that can be covalently bonded to the detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing a carbonate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety. It is understood that such moieties may be bonded directly to the provided compound or via a anchoring group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be bonded by click chemistry. In some embodiments, such moieties may be bonded by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are publicly known in the art, including those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57.

[0047] In this specification, the term “detectable portion” is used interchangeably with the term “label” and refers to any portion that can be detected, e.g., 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. Other detectable parts include luminescent groups and phosphorescent groups.

[0048] In this specification, the term “secondary label” refers to a portion of a protein, such as biotin and various protein antigens, that requires the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labeling, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in a non-radioactive fluorescence resonance energy transfer (FRET) process, producing a signal in which the second group is detectable.

[0049] In this specification, the terms "fluorescent label," "fluorescent dye," and "fluorescent phosphone" refer to a portion that absorbs light energy at a specified 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, and 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, Erythrosine, Fluorescein, FAM, Hid Examples include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lisamin Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0050] In this specification, the term “mass tag” means any portion that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophore-emitting tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives. The synthesis and utility of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, within a suitable mass range (100–2000 daltons) may be used as mass tags.

[0051] The terms “measurable affinity” and “measurable inhibition,” as used herein, mean a measurable change in IRAK protein kinase activity between a sample containing the compound or its composition and IRAK protein kinase of the present invention and an equivalent sample containing IRAK protein kinase in the absence of the compound or its composition.

[0052] 3. Description of exemplary embodiments: The compound of this invention has the following general structure, in which the cereblon-binding portion is bound to a ligand that binds to IRAK kinase: [ka] or a bifunctional molecule having a pharmaceutically acceptable salt thereof, wherein: IRAK is an IRAK binding site that can bind to one or more of IRAK1, IRAK2, IRAK3, or IRAK4; L is the divalent part that binds IRAK to LBM; and LBM is the ligase binding site. Ligase-binding site (LBM)

[0053] As described above, in a particular embodiment, the present invention relates to formula I: [ka] We provide compounds of or pharmaceutically acceptable salts thereof, where L and IRAK are as defined above and described in the embodiments herein: X 1 and X 2 These are independently covalent, -CR2-, -O-, -CF2-, [ka] is; or X 1 and X 2 -CR=CR-; X 3 and X 4 These are independently -CH2-, -C(O)-, -C(S)-, or [ka] and; Rings X and Y are independently fused rings selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings, each having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the nitrogen already illustrated in rings X and Y; R x and R y Each of them independently consists of hydrogen, deuterium, and R. zSelected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3; Each R is independently selected from hydrogen or, if necessary, a substituted group, and this optionally substituted group is C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same carbon or nitrogen, together as necessary with the atom between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this carbon or nitrogen; Each R z C 1~6 The groups are selected from substituted groups as needed, including 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2, 3, or 4.

[0054] As defined above and described herein, X 1 and X 2These are independently covalent, -CR2-, -O-, -CF2-, [ka] is; or X 1 and X 2 -CR = CR-.

[0055] In some embodiments, X 1 It is a covalent bond. In some embodiments, X 1 is -CR2-. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 is -O-. In some embodiments, X 1 is -CF2-. In some embodiments, X 1 teeth [ka] In some embodiments, X 2 It is a covalent bond. In some embodiments, X 2 is -CR2-. In some embodiments, X 2 is -CH2-. In some embodiments, X 2 is -O-. In some embodiments, X 2 is -CF2-. In some embodiments, X 2 teeth [ka] In some embodiments, X 1 and X 2 In some embodiments, X 1 and X 2 Therefore, -CH=CH-.

[0056] In some embodiments, X 1 and X 2 These are independently selected from the compounds shown in Table 1.

[0057] As defined above and described herein, X 3 and X 4 These are independently -CH2-, -C(O)-, -C(S)-, or [ka] That is the case.

[0058] In some embodiments, X 3 is -CH2-. In some embodiments, X 3 is -C(O)-. In some embodiments, X 3 is -C(S)-. In some embodiments, X 3 teeth [ka] In some embodiments, X 4 is -CH2-. In some embodiments, X 4 is -C(O)-. In some embodiments, X 4 is -C(S)-. In some embodiments, X 4 teeth [ka] That is the case.

[0059] In some embodiments, X 3 and X 4 The compounds are selected from those shown in Table 1.

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

[0061] In some embodiments, rings X and Y are independently fused rings selected from 5- to 6-membered saturated, partially unsaturated, or heteroaryl rings, each having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the nitrogen already illustrated in rings X and Y.

[0062] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] In some embodiments, ring X is [ka] That is the case.

[0063] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] In some embodiments, ring Y is [ka] That is the case.

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

[0065] As defined above and described herein, R x and R y Each of them independently consists of hydrogen, deuterium, and R. zSelected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3.

[0066] In some embodiments, R x is hydrogen. In some embodiments, R x is deutherium. In some embodiments, R x is R z In some embodiments, R x is a halogen. In some embodiments, R x is -CN. In some embodiments, R x is -NO2. In some embodiments, R x is -OR. In some embodiments, R x is -SR. In some embodiments, R x is -NR2. In some embodiments, R x is -S(O)2R. In some embodiments, R x is -S(O)2NR2. In some embodiments, R x is -S(O)R. In some embodiments, R x is -CFR2. In some embodiments, R x is -CF2R. In some embodiments, R x is -CF3. In some embodiments, R x is -CR2(OR). In some embodiments, R x is -CR2(NR2). In some embodiments, R xis -C(O)R. In some embodiments, R x is -C(O)OR. In some embodiments, R x is -C(O)NR2. 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 is -OC(O)NR2. In some embodiments, R x is -C(S)NR2. 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 is -N(R)C(O)NR2. In some embodiments, R x is -N(R)S(O)2R. In some embodiments, R x is -OP(O)R2. In some embodiments, R x is -OP(O)(OR)2. In some embodiments, R x is -OP(O)(OR)NR2. In some embodiments, R x is -OP(O)(NR2)2. In some embodiments, R x is -Si(OR)R2. In some embodiments, R x It is -SiR3.

[0067] In some embodiments, R y is hydrogen. In some embodiments, R y is deutherium. In some embodiments, R y is R z In some embodiments, R y is a halogen. In some embodiments, R y is -CN. In some embodiments, R y is -NO2. In some embodiments, R yis -OR. In some embodiments, R y is -SR. In some embodiments, R y is -NR2. In some embodiments, R y is -S(O)2R. In some embodiments, R y is -S(O)2NR2. In some embodiments, R y is -S(O)R. In some embodiments, R y is -CFR2. In some embodiments, R y is -CF2R. In some embodiments, R y is -CF3. In some embodiments, R y is -CR2(OR). In some embodiments, R y is -CR2(NR2). In some embodiments, R y is -C(O)R. In some embodiments, R y is -C(O)OR. In some embodiments, R y is -C(O)NR2. 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 is -OC(O)NR2. In some embodiments, R y is -C(S)NR2. 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 is -N(R)C(O)NR2. In some embodiments, R y is -N(R)S(O)2R. In some embodiments, R y is -OP(O)R2. In some embodiments, R y is -OP(O)(OR)2. In some embodiments, R yis -OP(O)(OR)NR2. In some embodiments, R y is -OP(O)(NR2)2. In some embodiments, R y is -Si(OR)R2. In some embodiments, R y It is -SiR3.

[0068] In a particular embodiment, R x and R y Each of these is selected from the compounds shown in Table 1.

[0069] As defined above and described herein, each R is independently selected from hydrogen or, if necessary, a substituted group, the optionally substituted group being C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally together with the atom between them to form optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl rings having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to this carbon or nitrogen.

[0070] In some embodiments, R is hydrogen. In some embodiments, R is a C which is substituted as needed. 1~6It is aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen optionally combine with an atom between them to form optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this carbon or nitrogen.

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

[0072] As defined above and described herein, each R z C 1~6 The group is optionally substituted, selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur-independently saturated or partially unsaturated heterocyclic rings with 4 to 7 members having 1 to 2 heteroatoms, and 5 to 6 members having 1 to 4 heteroatoms, unilaterally selected from nitrogen, oxygen, and sulfur.

[0073] In some embodiments, R z C is replaced as needed. 1~6 It is aliphatic. In some embodiments, R z R is a phenyl compound that is substituted as needed. In some embodiments, R z R is a optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R zIt is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0074] In a particular embodiment, R z The compounds are selected from those shown in Table 1.

[0075] As defined above and as 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 the compounds shown in Table 1.

[0078] As defined above and as 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 a particular embodiment, y is selected from the compounds shown in Table 1.

[0081] In some embodiments, the present invention is as shown, X 1 and X 2 is -CH2- and X 3 and X 4 is -C(O)-, and equation Ia-1: [ka] We provide a compound of formula I, where IRAK, L, ring X, ring Y, R, and a pharmaceutically acceptable salt thereof. x , R y Each of x, and y, both individually and in combination, is as defined above and as described in the embodiments herein.

[0082] In some embodiments, the present invention is as shown, X 1 and X 2 is -CH2-, X 3 and X 4 is -C(O)-, and ring Y is, [ka] And, equation Ia-2: [ka] We provide a compound of formula I, where IRAK, L, ring X, R, and a pharmaceutically acceptable salt thereof. x , R y Each of x, and y, both individually and in combination, is as defined above and as described in the embodiments herein.

[0083] In some embodiments, the present invention is as shown, X 1 and X 2 is -CH2-, X 3 and X 4 is -C(O)-, and ring X is, [ka] And, equation Ia-3: [ka] We provide a compound of formula I, where IRAK, L, ring Y, R, and a pharmaceutically acceptable salt thereof. x , R yEach of x, and y, both individually and in combination, is as defined above and as described in the embodiments herein.

[0084] In some embodiments, the present invention is as shown, X 1 and X 2 is -CH2-, X 3 and X 4 is -C(O)-, and ring X is, [ka] And ring Y is, [ka] And, equation Ia-4: [ka] We provide a compound of formula I, where IRAK, L, R x , R y Each of x, and y, both individually and in combination, is as defined above and as described in the embodiments herein.

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

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

[0087] In a particular embodiment, the present invention is such that IRAK is the IRAK4 coupling portion, thereby formula I-aa: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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; Ring B is a phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a 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 5- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; L 2 and L 3 Each of them is independent, covalently bonded, or C 1~3 A divalent linear or branched saturated or unsaturated hydrocarbon chain, where one to three methylene units in the chain are independently replaced as needed by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CF(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -CR=CR-; Each R 1 These are independently hydrogen, deutherium, and -R 5, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, or -C(O)NR2; Each R is independently a hydrogen, deuterium, or optionally substituted group, and this optionally substituted group is C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same atom, together as necessary with the atom between them, form a optionally substituted 4- to 11-membered saturated or partially unsaturated, carbocyclic or heterocyclic, monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring, which has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the atom to which they are bonded; Each R 2 These are independently hydrogen, deutherium, and -R 5 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 4 teeth, [ka] Selected from hydrogen, or optionally substituted groups, the optionally substituted group is C 1~6Selected 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 ring, or a 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 These are independently hydrogen, deutherium, and -R 5 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Each R 5 C 1~6 A optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic rings, or heterocyclic rings having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having one or four 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 carbocyclic or heterocyclic ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

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

[0091] As generally defined above, ring B is a phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a 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.

[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 a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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.

[0093] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] That is the case.

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

[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.

[0096] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] That is the case.

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

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

[0099] In some embodiments, L 2 L is a covalent bond. In some embodiments, L 2 C 1~3A divalent linear or branched saturated or unsaturated hydrocarbon chain, where one to three methylene units in the chain are independently replaced as needed with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CF(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -CR=CR-. In some embodiments, L 2 is C 1~3 It is aliphatic. In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is -C(D)(H)-. In some embodiments, L 2 is -C(D)2-. In some embodiments, L 2 is -CH2CH2-. In some embodiments, L 2 is -NR-. In some embodiments, L 2 is -CH2NR-. In some embodiments, L 2 is or -O-. In some embodiments, L 2 is -CH2O-. In some embodiments, L 2 is -S-. In some embodiments, L 2 is -OC(O)-. In some embodiments, L 2 is -C(O)O-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is -S(O)-. In some embodiments, L 2 is -S(O)2-. In some embodiments, L 2 is -NRS(O)2-. In some embodiments, L 2 is -S(O)2NR-. In some embodiments, L 2 is -NRC(O)-. In some embodiments, L 2 is -C(O)NR-. In some embodiments, L 2 is -OC(O)NR-. In some embodiments, L 2It is -NRC(O)O-.

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

[0101] In some embodiments, L 3 C 1~3 A divalent linear or branched saturated or unsaturated hydrocarbon chain, where one to three methylene units in the chain are independently replaced as needed with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CF(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -CR=CR-. In some embodiments, L 3 is C 1~3 It is aliphatic. In some embodiments, L 3 is -CH2-. In some embodiments, L 3 is -C(D)(H)-. In some embodiments, L 3 is -C(D)2-. In some embodiments, L 3 is -CH2CH2-. In some embodiments, L 3 is -NR-. In some embodiments, L 3 is -CH2NR-. In some embodiments, L 3 is or -O-. In some embodiments, L 3 is -CH2O-. 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, L3 is -C(O)-. In some embodiments, L 3 is -S(O)-. In some embodiments, L 3 is -S(O)2-. In some embodiments, L 3 is -NRS(O)2-. In some embodiments, L 3 is -S(O)2NR-. 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 It is -NRC(O)O-.

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

[0103] As generally defined above, each R 1 These are independently hydrogen, deutherium, and -R 5 , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), -CFR2, -CF3, -CR2(OR) , -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, -SF5, or [ka] That is the case.

[0104] In some embodiments, each R 1 R is independently hydrogen. In some embodiments, R 1 is deutherium. In some embodiments, each R 1 -R is independent. 5 In some embodiments, each R 1 R is independently a halogen. In some embodiments, each R 1 In some embodiments, each R 1 In some embodiments, each R 1 These are independently -OR. In some embodiments, each R 1 In some embodiments, each R 1 Independently, R is -NR2. In some embodiments, each R 1 Independently, each R is -S(O)2R. In some embodiments, each R 1 Independently, R is -S(O)2NR2. In some embodiments, each R 1 Independently, each R is -S(O)R. In some embodiments, each R 1 Independently, each R is -S(O)(NR)R. In some embodiments, each R 1 Independently, each R is -P(O)(OR)2. In some embodiments, each R 1 Independently, R is -P(O)(NR2)2. In some embodiments, each R 1 Independently, each R is -CF2(R). In some embodiments, each R 1 In some embodiments, each R 1 In some embodiments, each R 1 Independently, R is -CR2(OR). In some embodiments, each R 1 Independently, R is -CR2(NR2). In some embodiments, each R 1 Independently, each R is -C(O)R. In some embodiments, each R 1Independently, each R is -C(O)OR. In some embodiments, each R 1 Independently, R is -C(O)NR2. In some embodiments, each R 1 Independently, each R is -C(O)N(R)OR. In some embodiments, each R 1 Independently, each R is -OC(O)R. In some embodiments, each R 1 Independently, R is -OC(O)NR2. In some embodiments, each R 1 Independently, each R is -N(R)C(O)OR. In some embodiments, each R 1 Independently, each R is -N(R)C(O)R. In some embodiments, each R 1 Independently, R is -N(R)C(O)NR2. In some embodiments, each R 1 Independently, R is -N(R)S(O)2R. In some embodiments, each R 1 -N + (O - )R2. In some embodiments, each R 1 Independently, R is -OP(O)R2. In some embodiments, each R 1 Independently, R is -OP(O)(OR)2. In some embodiments, each R 1 Independently, each R is -OP(O)(OR)NR2. In some embodiments, each R 1 Independently, R is -OP(O)(NR2)2. In some embodiments, each R 1 Independently, R is -P(O)R2. In some embodiments, each R 1 In some embodiments, each R is independently -SiR3. 1 Independently, R is -Si(OR)R2. In some embodiments, each R 1 In some embodiments, each R 1 They are independent, [ka] That is the case.

[0105] In some embodiments, R 1 is -CHF2. In some embodiments, R 1 is -C(OH)(CH3)2. In some embodiments, R 1 It is -OMe.

[0106] As generally defined above, R 2 and R 3 Each of them independently consists of hydrogen, deuterium, and -R 5 , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR) , -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, -SF5, or [ka] That is the case.

[0107] In some embodiments, R 2 and R 3 Each of them is independently hydrogen. In some embodiments, R 2 and R 3 Each of them is independently a deuterium. In some embodiments, R 2 and R 3 Each of these is independent of -R 5 In some embodiments, R 2 and R 3 Each of them is independently a halogen. In some embodiments, R 2 and R3 Each of them is independently -CN. In some embodiments, R 2 and R 3 Each of them is independently -NO2. In some embodiments, R 2 and R 3 Each of them 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 -NR2. In some embodiments, R 2 and R 3 Each of them is independently -S(O)2R. In some embodiments, R 2 and R 3 Each of them is independently -S(O)2NR2. In some embodiments, R 2 and R 3 Each of them is independently -S(O)R. In some embodiments, R 2 and R 3 Each of them is independently -S(O)(NR)R. In some embodiments, R 2 and R 3 Each of these is independently -P(O)(OR)2. In some embodiments, R 2 and R 3 Each of them is independently -P(O)(NR2)2. In some embodiments, R 2 and R 3 Each of these is independently -CFR2. In some embodiments, R 2 and R 3 Each of them is independently -CF2(R). In some embodiments, R 2 and R 3 Each of them is independently -CF3. In some embodiments, R 2 and R 3 Each of them is independently -CR2(OR). In some embodiments, R 2 and R 3Each of them is independently -CR2(NR2). In some embodiments, R 2 and R 3 Each of them is independently -C(O)R. In some embodiments, R 2 and R 3 Each of them is independently -C(O)OR. In some embodiments, R 2 and R 3 Each of them is independently -C(O)NR2. In some embodiments, R 2 and R 3 Each of them is independently -C(O)N(R)OR. In some embodiments, R 2 and R 3 Each of them is independently -OC(O)R. In some embodiments, R 2 and R 3 Each of these is independently -OC(O)NR2. In some embodiments, R 2 and R 3 Each of them is independently -N(R)C(O)OR. In some embodiments, R 2 and R 3 Each of them is independently -N(R)C(O)R. In some embodiments, R 2 and R 3 Each of them is independently -N(R)C(O)NR2. In some embodiments, R 1 and R 2 Each of them is independently -N(R)S(O)2R. In some embodiments, R 2 and R 3 Each of these is independent of -N + (O - )R2. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)R2. In some embodiments, R 2 and R 3 Each of them is independently -OP(O)(OR)2. In some embodiments, R 2 and R 3Each of these is independently -OP(O)(OR)NR2. In some embodiments, R 2 and R 3 Each of these is independently -OP(O)(NR2)2. In some embodiments, R 2 and R 3 Each of them is independently -P(O)R2. In some embodiments, R 2 and R 3 Each of them is independently -SiR3. In some embodiments, R 2 and R 3 Each of them is independently -Si(OR)R2. In some embodiments, R 2 and R 3 Each of them is independently -SF5. In some embodiments, R 2 and R 3 Each of them is independent, [ka] That is the case.

[0108] In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is -CF3. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0109]

[0110] In some embodiments, R 1 , R 2 , and R 3 Each of these is independently selected from those shown in Table 1 below.

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

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

[0113] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0114] As generally defined above, ring D is a phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a 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.

[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 a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 shown in Table 1 below.

[0117] As generally defined above, each R is independently a hydrogen or optionally substituted group, and this optionally substituted group is C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom may optionally combine with the atom between them to form optionally substituted 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl rings having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the atom to which they are bonded.

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

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

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

[0121] In some embodiments, each R 5 C 1~6 A group selected from aliphatic groups, optionally substituted. In some embodiments, each R 5 R is independently a phenyl compound that is substituted as needed. In some embodiments, each R 5R is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R 5 It is 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 The option is selected from those shown 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, m and p are independently 0. In some embodiments, m and p are independently 1. In some embodiments, m and p are independently 2. In some embodiments, m and p are independently 3. In some embodiments, m and p are independently 4.

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

[0128] In some embodiments, the present invention has IRAK as shown, with formula I-aa-1: [ka] We provide a compound of formula Ia-1, where L, ring X, ring Y, and R, or a pharmaceutically acceptable salt thereof. x , R y x, y, L 2 , L 3 , ring A, ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0129] In some embodiments, the present invention has IRAK as shown, with formula I-aa and formula I-aa-2: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 2 , L 3 , ring A, ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0130] In some embodiments, the present invention has IRAK as shown, with formula I-aa and formula I-aa-3: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring B, ring C, R 1 , R 2 , R 4Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0131] In some embodiments, the present invention has IRAK as shown, with formula I-aa-4: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 2 , L 3 , ring A, ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0132] In some embodiments, the present invention is such that IRAK is of formula I-aa, in formula I-aa, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and equation I-aa-5: [ka] We provide a compound of formula Ia-1, where L, ring X, ring Y, and R, or a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0133] In some embodiments, the present invention is such that IRAK is of formula I-aa, in formula I-aa, as shown, ring A is cyclohexylenyl, and L 2The bond is covalent, and equation I-aa-6: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0134] In some embodiments, the present invention is such that IRAK is of formula I-aa, in formula I-aa, as shown, ring A is cyclohexylenyl, and L 2 This is a covalent bond, and equation I-aa-7: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0135] In some embodiments, the present invention is such that IRAK is of formula I-aa, in formula I-aa, as shown, ring A is cyclohexylenyl, and L 2 This is a coolant bond, and formula I-aa-8: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 3 , ring B, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0136] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-9: [ka] We provide compounds of formula Ia-4, where L, ring X, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0137] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The coolant bond is and ring B is indazolyl, and formula I-aa-10: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0138] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-11: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0139] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The coolant bond is and ring B is indazolyl, and formula I-aa-12: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0140] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is 6-azindazolyl, and formula I-aa-13: [ka] We provide compounds of formula Ia-4, where L, ring X, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0141] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The coolant bond is and ring B is 6-azindazolyl, and formula I-aa-14: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0142] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is 6-azaidazolyl, and formula I-aa-15: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0143] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The coolant bond is and ring B is 6-azindazolyl, and formula I-aa-16: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0144] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-17: [ka] We provide compounds of formula Ia-4, where L, ring X, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0145] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-18: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0146] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-19: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1, R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0147] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-20: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0148] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is pyrazolyl, and formula I-aa-21: [ka] We provide compounds of formula Ia-4, where L, ring X, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0149] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is pyrazolyl, and formula I-aa-22: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0150] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is pyrazolyl, and formula I-aa-23: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0151] In some embodiments, the present invention has IRAK of formula I-aa, where, as shown, ring A is cyclohexylenyl, and L 2 The bond is covalent, and ring B is pyrazolyl, and formula I-aa-24: [ka] We provide compounds of formula Ia-4, where L, R x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0152] In some embodiments, the present invention is characterized in that x is 1 and R x is methyl, and IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-25: [ka] We provide compounds of formula Ia-4, where L, ring X, ring Y, and R, or pharmaceutically acceptable salts thereof. y , y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0153] In some embodiments, the present invention is characterized in that x is 1 and R x is methyl, and IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-26: [ka] We provide a compound of formula Ia-2, where L is a ring X, R is a pharmaceutically acceptable salt thereof. y , y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0154] In some embodiments, the present invention is characterized in that x is 1 and R x is methyl, and IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-27: [ka] We provide compounds of formula Ia-3, where L, ring Y, and R, or pharmaceutically acceptable salts thereof. y , y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0155] In some embodiments, the present invention is characterized in that x is 1 and R x is methyl, and IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-28: [ka] We provide compounds of formula Ia-4, where L, R y , y, L 3 , ring C, R1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0156] In some embodiments, the present invention is characterized in that L is [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-29: [ka] We provide compounds of formula Ia-4, where ring X, ring Y, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0157] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-30: [ka] We provide compounds of formula Ia-4, where ring X, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0158] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-31: [ka] We provide compounds of formula Ia-4, where ring Y, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0159] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is benzothiazolyl, and formula I-aa-32: [ka] We provide a compound of formula Ia-4, which provides a compound of or a pharmaceutically acceptable salt thereof, where Rx , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0160] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-33: [ka] We provide compounds of formula Ia-4, where ring X, ring Y, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0161] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-34: [ka] We provide compounds of formula Ia-4, where ring X, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0162] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-35: [ka] We provide compounds of formula Ia-4, where ring Y, R, and a pharmaceutically acceptable salt thereof. x , R y x, y, L 2 , L 3 , ring A, ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0163] In some embodiments, the present invention is that L [ka] And IRAK is formula I-aa, and in formula I-aa, as shown, ring A is cyclohexylenyl, L 2 The bond is covalent, and ring B is indazolyl, and formula I-aa-36: [ka] We provide a compound of formula Ia-4, which provides a compound of or a pharmaceutically acceptable salt thereof, where R x , R y x, y, L 3 , ring C, R 1 , R 2 , R 4 Each of , n, and m, both individually and in combination, is as defined above and described in the embodiments herein.

[0164] In certain embodiments, the present invention relates to IRAK as an IRAK-4 inhibitor. [ka] [ka] Therefore, equations I-dd-1 or I-dd-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: A is a heteroaryl, aryl, heterocycloalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, or cycloalkyl-NR as needed. x - Heterocycloalkyl-NRs as needed x - aryl-NR replaced as needed x - Heteroaryl-NRs substituted as needed x- optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted aryl-O-, or optionally substituted heteroaryl-O-; for example, here each optional substituent is independently R z It indicates 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 (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl-NR x - Heterocycloalkyl-NRs as needed x - aryl-NR replaced as needed x - Heteroaryl-NRs substituted as needed x - optionally substituted cycloalkyl-O-, optionally substituted heterocycloalkyl-O-, optionally substituted aryl-O-, optionally substituted heteroaryl-O-; for example, here each optional substituent is independently R y It indicates the existence of; Q is either absent or optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, -NR3R4, -O-R3, or -SR; for example, where each optional substituent is independently R z It indicates the existence of; W is either N or CH; R1 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 -(CH2) m -R2; for example, here each required substituent independently represents halo, hydroxy, alkoxy, amino, nitro, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; R2 is hydrogen, -NR a R b , alkoxy, hydroxy, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; for example, here each optional substituent is independently R y It indicates the existence of; Each of R3 and R4 is independently selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, and optionally substituted (heterocycloalkyl)alkyl; for example, each optional substituent is independently selected from alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, nitro, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, and (heteroaryl)alkyl; R a and R b Each of them is independently selected from hydrogen, alkyl, aminoalkyl, acyl and heterocyclyl; or R a and R bThese, together with the nitrogen atoms to which they are bonded, form a ring that is substituted as needed; R x These are hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl, or cycloalkyl; R y and R z Each of these is independently selected from hydroxy, hydroxyalkyl, halo, alkyl, oxo, haloalkyl, alkoxy, alkenyloxy, amino, nitro, cyano, -SH, -S(alkyl), glycinate, ester, thioester, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, and (heteroaryl)alkyl; wherever necessary, here 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 These, together with the atoms to which they are bonded, form alkyl chains having 1 to 10 carbon atoms; wherever necessary, 1 to 3 carbon atoms are replaced by O, NH, or S; m is 1, 2, or 3; and n is either 1 or 2; As defined and described in WO 2017 / 009798 and US 2018 / 0201609, each of these in whole is incorporated herein by reference.

[0165] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, formulas I-ee-1, I-ee-2, I-ee-3, or I-ee-4 respectively: [ka] Provided is a compound of formula I which forms a compound 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 ; R 1 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~6 cycloalkyl, a 3- to 6-membered saturated heterocyclyl, halo, -CN, -C(R<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyls and 3- to 6-membered saturated heterocyclines have one or more R 10 It is replaced as needed; or two R 1 The substituents, together with the atoms between them, form C 5~7 It forms a cycloalkyl or saturated 5- to 7-membered heterocyclic ring, where this C 5~7 Cycloalkyl or saturated 5- to 7-membered heterocyclic rings have one or more R 15 It is replaced as needed; R 1a In each existence, H and C are independent. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl are selected, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyls, 3- to 6-membered monocyclic carbocyclyls, and 3- to 6-membered monocyclic heterocyclyls each contain one or more R atoms. 10 It is replaced independently as needed; R 10 In each existence, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 10a ,-C(O)N(R 10a )2, -NO2, -N(R 10a )2, -N(R 10a )C(O)R 10a , -N(R 10a )C(O)2R 10a , -N(R10a )C(O)N(R 10a )2, -N(R 10a )S(O)2R 10a , -OR 10a , -OC(O)R 10a , -OC(O)N(R 10a )2, -SR 10a , -S(O)R 10a , -S(O)2R 10a , -S(O)N(R 10a )2, and -S(O)2N(R 10a )2 is selected from; R 10a is, independently in each occurrence, H and C 1~6 alkyl is selected from, where this C 1~6 alkyl is optionally substituted with one or more halos; R 15 is, independently in each occurrence, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, a 3- to 6-membered carbocyclic, a 3- to 6-membered heterocyclic, halo, -CN, -C(R 15a )=NR(OR 15a )、-C(R 15a )=N(R 15a )、-C(O)R 15a 、-C(O)2R 15a 、-C(O)N(R 15a )2、-NO2、-N(R 15a )2、-N(R 15a )C(O)R 15a 、-N(R 15a )C(O)2R 15a 、-N(R 15a )C(O)N(R[[ID=6८]] 15a )2、-N(R 15a )S(O)2R 15a 、-OR 15a 、-OC(O)R 15a 、-OC(O)N(R 15a )2、-SR 15a 、-S(O)R 15a 、-S(O)2R 15a 、-S(O)N(R 15a )2、and -S(O)2N(R 15a) Selected from 2; R 15a In each existence, H and C are independent of each other. 1~6 Selected from alkyl, here this C 1~6 Alkyl atoms are substituted as needed with one or more halos; R 2 H, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 2a ,-C(O)N(R 2a )2, -NO2, -N(R 2a )2, -N(R 2a )C(O)R 2a , -N(R 2a )C(O)2R 2a , -N(R 2a )C(O)N(R 2a )2, -N(R 2a )S(O)2R 2a , -OR 2a -OC(O)R 2a ,-OC(O)N(R 2a )2, -SR 2a ,-S(O)R 2a -S(O)2R 2a ,-S(O)N(R 2a )2, and -S(O)2N(R 2a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl have one or more R 20 It is replaced as needed; R 2a In each existence, H and C are independent of each other. 1~6 Selected from alkyl, here this C 1~6 Alkyl groups have one or more R atoms in each presence.20 It is replaced independently as needed; R 20 In each existence, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 20a ,-C(O)N(R 20a )2, -NO2, -N(R 20a )2, -N(R 20a )C(O)R 20a , -N(R 20a )C(O)2R 20a , -N(R 20a )C(O)N(R 20a )2, -N(R 20a )S(O)2R 20a , -OR 20a -OC(O)R 20a ,-OC(O)N(R 20a )2, -SR 20a ,-S(O)R 20a -S(O)2R 20a ,-S(O)N(R 20a )2, and -S(O)2N(R 20a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Cycloalkyls and 3- to 7-membered saturated heterocyclines each have one or more R atoms in their presence. 25 It is replaced independently as needed; R 20a In each existence, H and C are independent of each other. 1~6 Selected from alkyl, here this C 1~6 Alkyl is R 25 It is replaced as needed; R 25 This includes halo and -OR 25aSelected from; R 25a H and C 1~6 Selected from alkyl groups; R 3 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 3a ,-C(O)N(R 3a )2, -NO2, -N(R 3a )2, -N(R 3a )C(O)R 3a , -N(R 3a )C(O)2R 3a , -N(R 3a )C(O)N(R 3a )2, -N(R 3a )S(O)2R 3a , -OR 3a -OC(O)R 3a ,-OC(O)N(R 3a )2, -SR 3a ,-S(O)R 3a -S(O)2R 3a ,-S(O)N(R 3a )2, and -S(O)2N(R 3a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyls and 3- to 6-membered saturated heterocyclines have one or more R 30 It is replaced as needed; R 3a In each existence, H and C are independent. 1~6 Selected from alkyl groups, 3- to 6-membered carbocyclyl groups, and 3- to 6-membered heterocyclyl groups, where this C 1~6Alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl each have one or more R groups in their presence. 30 It is replaced independently as needed; R 30 In each existence, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 30a ,-C(O)N(R 30a )2, -NO2, -N(R 30a )2, -N(R 30a )C(O)R 30a , -N(R 30a )C(O)2R 30a , -N(R 30a )C(O)N(R 30a )2, -N(R 30a )S(O)2R 30a , -OR 30a -OC(O)R 30a ,-OC(O)N(R 30a )2, -SR 30a ,-S(O)R 30a S(O)2R 30a ,-S(O)N(R 30a )2, and -S(O)2N(R 30a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyls, 3- to 6-membered carbocyclyls, and 3- to 6-membered heterocyclyls each contain one or more R atoms. 35 It is replaced independently as needed; R 30a In each existence, H and C are independent of each other. 1~4 Selected from alkyl, where C 1~4 Alkyl groups consist of one or more R 35It is replaced as needed; R 35 In each existence, independently, the halo and -OR 35a Selected from; R 35a In each existence, H and C are independent of each other. 1~6 Selected from alkyl groups; R 4 H, Halo, C 1~6 Alkyl, N(R 4a )2, and -OR 4a Selected from; and R 4a In each existence, H and C are independent of each other. 1~6 Selected from alkyl groups; As defined and described in WO 2016 / 011390 and US 2017 / 0204093, each of these in whole is incorporated herein by reference.

[0166] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equations I-ff-1, I-ff-2, I-ff-3, or I-ff-4: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is selected from phenyl and 5-membered or 6-membered heteroaryls; Ring B is selected from phenyl and 5-membered or 6-membered heteroaryl groups; 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 CR2 and; R 1 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Halo, -CN, -C(R la )=NR(OR la ), -C(R la )=N(R la ), -C(O)R la -C(O)2R la ,-C(O)N(R la )2, -NO2, -N(R la )2, -N(R la )C(O)R la , -N(R la )C(O)2R la , -N(R la )C(O)N(R la )2, -N(R la )S(O)2R la , -OR la -OC(O)R la ,-OC(O)N(R la )2, -SR la ,-S(O)R la -S(O)2R la ,-S(O)N(R la )2, and -S(O)2N(R la ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl contains one or more R 10 It is replaced as needed; R la In each existence, independently, H or C 1~6 Selected from alkyl, here this C 1~6 Alkyl groups have one or more R atoms in each presence. 10 It is replaced independently as needed; R 10 These are independently of each entity: Halo, -CN, -C(R 10a )=NR(OR) 10a , -C(R 10a )=N(R 10a ), -C(O)R 10a-C(O)2R 10a ,-C(O)N(R 10a )2, -NO2, -N(R 10a )2, -N(R 10a )C(O)R 10a , -N(R 10a )C(O)2R 10a , -N(R 10a )C(O)N(R 10a )2, -N(R 10a )S(O)2R 10a , -OR 10a -OC(O)R 10a ,-OC(O)N(R 10a )2, -SR 10a ,-S(O)R 10a -S(O)2R 10a ,-S(O)N(R 10a )2, and -S(O)2N(R 10a ) Selected from 2; R 10a In each existence, H and C are independent of each other. 1~6 Selected from alkyl groups, where this C1-6 alkyl group is substituted as needed with one or more halos; R is H, C1-6 alkyl, C2-6 alkenyl, C2-6 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)2R 2a ,-C(O)N(R 2a )2, -NO2, -N(R 2a )2, -N(R 2a )C(O)R 2a , -N(R 2a )C(O)2R 2a , -N(R 2a )C(O)N(R 2a )2, -N(R 2a )S(O)2R 2a , -OR 2a -OC(O)R 2a ,-OC(O)N(R 2a )2, -SR 2a,-S(O)R 2a -S(O)2R 2a ,-S(O)N(R 2a )2, and -S(O)2N(R 2a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenyls, C2-6 alkynyls, 3- to 7-membered carbocyclyls, and 3- to 7-membered heterocyclyls have one or more R 20 It is replaced as needed; R 2a In each existence, H and C are independent of each other. 1~6 Selected from alkyl, here this C 1~6 The alkyl group is independently substituted as needed with one or more R20 atoms in each presence; R 20 In each occurrence, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2R 20a ,-C(O)N(R 20a )2, -N02, -N(R 20a )2, -N(R 20a )C(O)R 20a , -N(R 20a )C(O)2R 20a , -N(R 20a )C(O)N(R 20a )2, -N(R 20a )S(O)2R 20a , -OR 20a -OC(O)R 20a ,-OC(O)N(R 20a )2, -SR 20a ,-S(O)R 20a -S(O)2R 20a ,-S(O)N(R 20a )2, and -S(O)2N(R 20a) Selected from 2, and here this C 1~6 Alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~7 Cycloalkyls and 3- to 7-membered saturated heterocyclines each have one or more R atoms in their presence. 25 It is replaced independently as needed; R 20a In each existence, H and C are independent of each other. 1~6 Selected from alkyl, here this C 1~6 Alkyl is R 25 It is replaced as needed; R 25 This includes halo and -OR 25a Selected from; R 25a H and C 1~6 Selected from alkyl groups; R is C 1~6 Alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~6 Cycloalkyl, 3-6 member saturated heterocyclyl, halo, -CN, -C(R) 3a )=NR(OR 3a ), -C(R 3a )=N(R 3a ), -C(O)R 3a -C(O)2R 3a ,-C(O)N(R 3a )2, -NO2, -N(R 3a )2, -N(R 3a )C(O)R 3a , -N(R 3a )C(O)2R 3a , -N(R 3a )C(O)N(R 3a )2, -N(R 3a )S(O)2R 3a , -OR 3a -OC(O)R 3a ,-OC(O)N(R 3a )2, -SR 3a ,-S(O)R 3a -S(O)2R 3a ,-S(O)N(R 3a )2, and -S(O)2N(R 3a ) Selected from 2, and here this C 1~6Alkyl, C 2~6 Alkenyl, C2-6 Alkinyl, C 3~6 Cycloalkyls and 3- to 6-membered saturated heterocyclines have one or more R 30 It is replaced as needed; R 3a In each existence, H and C are independent. 1~6 Selected from alkyl groups, 3- to 6-membered carbocyclyl groups, and 3- to 6-membered heterocyclyl groups, where this C 1~6 Alkyl, 3-6 membered carbocyclyl, and 3-6 membered heterocyclyl each have one or more R groups in their presence. 30 It is replaced independently as needed; R 30 In each occurrence, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, halo, -CN, -C(R) 30a )=NR(OR 30a ), -C(R 30a )=N(R 30a ), -C(O)R 30a -C(O)2R 30a ,-C(O)N(R 30a )2, -NO2, -N(R 30a )2, -N(R 30a )C(O)R 30a , -N(R 30a )C(O)2R 30a , -N(R 30a )C(O)N(R 30a )2, -N(R 30a )S(O)2R 30a , -OR 30a -OC(O)R 30a ,-OC(O)N(R 30a )2, -SR 30a ,-S(O)R 30a -S(O)2R 30a ,-S(O)N(R 30a )2, and -S(O)2N(R 30a ) Selected from 2, and here this C 1~6 Alkyl, C 2~6 Alkenil, C2~6 Alkinyl, 3-6 membered carbocyclyl, and 3-6 membered heterocyclyl each have one or more R in their respective presences. 35 It is replaced independently as needed; R 30a In each existence, H and C are independent of each other. 1~4 Selected from alkyl, where C 1~4 Alkyl groups consist of one or more R 35 It is replaced as needed; R 35 In each existence, independently, the halo and -OR 35a Selected from; and R 35a In each existence, H and C are independent of each other. 1~6 Selected from alkyl groups; As defined and described in WO 2017 / 127430, the entire text is incorporated herein by reference.

[0167] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-gg-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and imidazolo[4,5-d]pyrimidinyl, where this heteroaryl is bonded to the pyridinyl group of the compound of formula (I) by nitrogen ring atoms in this heteroaryl, and this heteroaryl has 0 to 2 R b It has been replaced with; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl, or dihydroisoxazolyl, each of which is R a It has been replaced with; R3 is C 2~3 Alkyl, C 2~3 Fluoroalkyl, C 3~4 A hydroxyalkyl or cyclic group, and this cyclic group is C 3~6 Selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where this cyclic group is F, -OH, C 1~2 Substituting with 0 to 2 substituents independently selected from alkyl and -CH2CHF2; R a teeth: (i) H, F, C1, -OH, -CN, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~4 Cyanoalkyl, C 1~6 Hydroxyalkyl, C 1~5 Hydroxyfluoroalkyl, C 2~4 Alkenil, C 1~6 Aminoalkyl, -(CH2) 1~3 NHR y ,-(CH2) 1~3 NR y R y -CH2CH(OH)(phenyl), -CH(CH2OH)(phenyl), -CH2CH(OH)CH2(phenyl), -CH2CH(OH)CH2O(methoxyphenyl), -CH2CH(NH2)CH2(phenyl), -(CH2CH2O)4H, -(CH2) 1~3 O(C 1~3 Alkyl), -CH2CH(OH)CH2O(C 1~3 Alkyl), -CH2C(O)(C 1~3 Alkyl), -CH2C(O)NR y R y ,-(CH2) 1~3 NR y C(O)(C 1~3 Alkyl), -CH2C(O)O(C 1~3 Alkyl), -C(O)NH2, -CH2NRy C(O)NH2, -(CH2) 1~2 NR y C(O)O(C 1~2 Alkyl), -(CR y R y ) 1~5 OC(O)CH2NR y R y , -CH2CH2S(O)2CH3, -CH2S(O)2(C 1~3 Alkyl), -CH2S(O)2(phenyl), or -NH(aminocyclohexyl); or (ii) -(CH2) 0~3 R z or -(CH2) 0~1 C(O)R z And here R z C 3~6 Cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, dioxopyrimidinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxolanil, or 8-azabicyclo[3.2.1]octanyl, each being F, -CN, -OH, or -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)CH2(C 3~6 Cycloalkyl), -C(O)O(C 1~4Alkyl), -NH(C 1~4 Alkyl), -NH(C 1~3 Fluoroalkyl), -NHC(O)CH3, -NHC(O)O(C 1~3 Alkyl), -NHC(O)OC(CH3)3, -S(O)2(C 1~3 Alkyl), -OS(O)2(C 1~3 Substituting with 0 to 4 substituents independent of alkyl, methyloxadiazolyl, and pyrimidinyl; Each R b These are independently selected from H, Cl, -CN, -NH2, and -C(O)NH2, where this heteroaryl is bonded to the pyridinyl group by the nitrogen atom in this heteroaryl; and Each R y H or C 1~2 It is alkyl; As defined and described in WO 2016 / 210034 and US 2018 / 0186799, each of these in whole is incorporated herein by reference.

[0168] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, formulas I-hh-1, I-hh-2, I-hh-3, or I-hh-4: [ka] [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X1, X2, and X3 each operate independently, CR 2 or N; A is O, S, S(O), or S(O)2; Z1 is a heteroaryl, heterocycloalkyl, aryl, cycloalkyl, (heterocycloalkyl)alkyl-, aralkyl-, heteroaralkyl-, (cycloalkyl)alkyl-, aryloxy-, heteroaryloxy-, heterocycloalkyloxy-, cycloalkyloxy-, aryl-NR'-, heteroaryl-NR'-, heterocycloalkyl-NR'-, cycloalkyl-NR'-, aryl-S-, heteroalkyl aryl-S-, optionally substituted heterocycloalkyl-S-, optionally substituted cycloalkyl-S-, optionally substituted (cycloalkyl)alkyl-NR'-, optionally substituted aralkyl-NR'-, optionally substituted (heterocycloalkyl)alkyl-NR'-, optionally 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 (heterocycloalkyl)alkyl-O-, optionally substituted heteroaralkyl-O-; for example, here each optional substituent is independently R x It indicates the existence of; Z2 is absent or substituted as necessary: ​​cycloalkyl, substituted as necessary: ​​aryl, substituted as necessary: ​​heterocycloalkyl, substituted as necessary: ​​heteroaryl, substituted as necessary: ​​aryloxy-, substituted as necessary: ​​heteroaryloxy-, substituted as necessary: ​​cycloalkyloxy-, substituted as necessary: ​​heterocycloalkyloxy-, substituted as necessary: ​​(cycloalkyl)alkyl-, substituted as necessary: ​​aralkyl-, substituted as necessary: ​​(heterocycloalkyl)alkyl-, substituted as necessary: ​​heteroaralkyl-, substituted as necessary: ​​(cycloalkyl)alkyl-NR''-, as necessary 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, here each optional substituent is independently R y It indicates the existence of; Z3 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, 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)-NR'”-, optionally substituted aryl-NR'”-, optionally substituted heteroaryl-NR'”-, optionally substituted heterocycloalkyl-NR'”-, optionally substituted aryl-S-, optionally substituted hetero aryl-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 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, here each optional substituent is independently R z It indicates the existence of; Each R 2These are independently hydrogen, alkyl, haloalkyl, halo, cyano, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl-, 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 Selected from -O-R3 and -S-R3; for example, here each required substituent independently represents alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, -SH, -S(alkyl), cyano, amide, 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 of these independently includes 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-, heteroaralkyl-, and -NR. a R bSelected from -O-R4 or -S-R4; optionally, here this cycloalkyl, aryl, heterocycloalkyl, and heteroaryl is further substituted with one or more substituents selected from halo, haloalkyl, amino, hydroxy, alkyl, cyano, nitro, alkenyl, aminoalkyl, hydroxyalkyl, and haloalkoxy; R a and R b Each is independently selected from 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, here this cycloalkyl, heterocycloalkyl, aryl and heteroaryl are further substituted with one or more substituents selected from alkyl, halo, alkenyl, cyano, hydroxy, hydroxyalkyl, alkoxy, amino and nitro; or R a and R b These, together with the atoms to which they are bonded, form 3- to 8-membered rings as needed, and R3 and R4 are each independently selected from hydrogen, alkyl, aminoacyl, phosphate, phosphonate, alkyl phosphate, alkoxycarbonyl, cycloalkyl, (cycloalkyl)alkyl-, aryl, heteroaryl, heterocycloalkyl, aralkyl-, heteroaralkyl, and (heterocycloalkyl)alkyl-; As defined and described in WO 2017 / 009806 and US 2018 / 0208605, each of these in whole is incorporated herein by reference.

[0169] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-ii-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is either CR or N; A is either O, S, SO2, SO, -NRC(O), -NRSO2, or N(R); or A does not exist. R 3 is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; or If A is -NRC(O), -NRSO2, or N(R); R and R 3 These, together with the atoms to which each is bonded, can form a 3- to 7-membered heterocyclic ring 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 may be substituted as needed; X' is either 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 a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of these is substituted as necessary; R 1 -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; R aIt is either nonexistent, or -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; 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, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; R b It is either nonexistent, or -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R independently consists of hydrogen and C. 1~6 aliphatic, C 3~10 An aryl ring, a 3- to 8-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered heterocyclic ring 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 may be substituted as necessary; or Two R groups on the same atom, together with the atom they are bonded to, become C 3~10 They form aryl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 3- to 7-membered heterocyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered monocyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of these is substituted as necessary; As defined and described in WO 2016 / 081679 and US 2016 / 0145252, each of these in whole is incorporated herein by reference.

[0170] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equations I-jj-1 or I-jj-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is either NH or O; b is either 0 or 1; n is 0, 1, 2, 3, or 4; R1 and R2 are independently H, (C1-C4) alkyl, and heterocyclyl, or R1 and R2 together with the nitrogen to which they are bonded may form a monocyclic or bicyclic (condensed, bridged, or spirocyclic) heterocycle containing 3 to 8 carbon atoms, and optionally containing one or two further heteroatoms selected from N, O, and S in addition to this nitrogen, and this alkyl and heterocycle is R a Substituted as needed with one or more substituents selected from; R3 is an (C1-C4) alkyl group, where two adjacent alkyl groups can combine to form a bridged region of 3-6 carbon atoms; R4 is either non-existent or contains a halo or O b (C1~C4) alkyl; R5 is selected from C1-C4 alkyl and C2-C4 alkenyl groups, and these are R b Substituted as needed with one or more substituents selected from; R6 is either absent, a halo, or an O(C1-C4) alkyl group; R a is halo, oxo, OH, O b (C1-C4)alkyl, CF3, SO2(C1-C4)alkyl, or heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents independently selected from F and (C1-C4)alkyl; and R b These are independently OH, Halo, O b Selected from (C1-C4) alkyl and CN; As defined and described in WO 2016 / 053769 and US 2017 / 0247388, each of these in whole is incorporated herein by reference.

[0171] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equations I-kk-1 or I-kk-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 if B is S, then D is CH, E is N, F is CH, G is N, and J is C; X is O, S, CH2, or N; m is 0 or 1; n is 0, 1 or 2; Ring A is pyridinyl, pyrazolyl, thiophenyl, furanyl, or phenyl; R1 is independently selected from (C1-C4)alkyl, pyrimidine, piperidine, and phenyl, respectively, and each is (C1-C4)alkyl, OH, halo, O(C1-C4)alkyl, methylpiperidine, S(O)2R c , C(O)N(R b )2, or C(O)O(C1~C4)alkyl as needed; R2 is either absent or H, and R3 is independently selected from (C1-C4) alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, each being halo, OH, oxo, or N(R) b )2, optionally substituted with one or more substituents independently selected from oxopyrrolidinyl or morpholinyl, or R2 and R3 together with the nitrogen to which they are bonded may form piperazine or morpholine, each optionally substituted with an oxo; R4 is independently either H or methyl; R b These are independently selected from H and (C1-C4) alkyl groups; and R c It is methyl; As defined and described in WO 2016 / 144844 and US 2018 / 0051027, each of these in whole is incorporated herein by reference.

[0172] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equations I-kk'-1 or I-kk'-2 respectively: [ka] We provide compounds of formula I, forming a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in embodiments herein, and each of the variable A, B, D, E, F, G, J, X, R1, R2, R3 and n is as defined and described in WO 2016 / 144844 and US 2018 / 0051027, each of these in whole being incorporated herein by reference. Such IRAK4 inhibitors are well known to those skilled in the art and include those 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 present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equations I-ll-1 or I-ll'-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is an aryl or heterocyclyl; n is 0, 1, 2, 3, or 4; R1 is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocyclyl, CF3, CHF2, CN, and halo, where these alkyl, cycloalkyl, and heterocyclyl are optionally substituted with halo, OH, CH3, and OCH3; R2 is H, and R3 is independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R) b)2, or substituted with morpholinyl as needed, or R2 and R3 together with the nitrogen to which they are bound may form a heterocycline, this heterocycline is R a Substituted as needed with one or more substituents selected from; R a The alkyl group is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, CF3, CHF2, OH, halo, and NH2, and this alkyl group is optionally substituted with (C3-C6) cycloalkyl and CF3; and R b These are independently selected from H and (C1-C4) alkyl groups; As defined and described in WO 2016 / 144847 and US 2018 / 0051029, each of these in whole is incorporated herein by reference.

[0174] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, formulas I-mm-1 or I-mm'-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is an aryl or heterocyclyl; n is 0, 1, 2, 3, or 4; R1 is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocyclyl, CF3, CHF2, CN, and halo, where this alkyl, cycloalkyl, and heterocyclyl is optionally substituted with halo, OH, CH3, and OCH3; R2 is H, and R3 is independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R) b )2, or substituted with morpholinyl as needed, or R2 and R3 together with the nitrogen to which they are bound may form a heterocycline, this heterocycline is R a Substituted as needed with one or more substituents selected from; R a The alkyl group is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, CF3, CHF2, OH, halo, and NH2, and this alkyl group is optionally substituted with (C3-C6) cycloalkyl or CF3; and R b These are independently selected from H and (C1-C4) alkyl groups; As defined and described in WO 2016 / 144846 and US 2018 / 0051028, each of these in whole is incorporated herein by reference.

[0175] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equations I-nn-1 or I-nn'-2 respectively: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is an aryl or heterocyclyl; n is 0, 1, 2, 3, or 4; R1 is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocyclyl, CF3, CHF2, CN, and halo, where these alkyl, cycloalkyl, and heterocyclyl are optionally substituted with halo, OH, CH3, and OCH3; R2 is H, and R3 is independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, and heterocyclyl, each containing one or more halo, OH, N(R) b )2, or substituted with morpholinyl as needed, or R2 and R3 together with the nitrogen to which they are bound may form a heterocycline, this heterocycline is R a Substituted as needed with one or more substituents selected from; R a The alkyl group is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, CF3, CHF2, OH, halo, and NH2, and this alkyl group is optionally substituted with (C3-C6) cycloalkyl and CF3; and R b These are independently selected from H and (C1-C4) alkyl groups; As defined and described in WO 2016 / 144848 and US 2018 / 0051030, each of these in whole is incorporated herein by reference.

[0176] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, formulas I-oo-1 or I-oo'-2 respectively: [ka] [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is an aryl or heterocyclyl; n is 0, 1, 2, 3, or 4; R1 is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocyclyl, CF3, CHF2, CN, and halo, where these alkyl, cycloalkyl, and heterocyclyl are optionally substituted with halo, OH, CH3, and OCH3; R2 is H, and R3 is independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl and heterocyclyl, each containing one or more halo, OH, N(R) b )2, or substituted with morpholinyl as needed, or R2 and R3 together with the nitrogen to which they are bound may form a heterocycline, this heterocycline is R a Substituted as needed with one or more substituents selected from; R a The alkyl group is independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, CF3, CHF2, OH, halo, and NH2, and this alkyl group is optionally substituted with (C3-C6) cycloalkyl and CF3; and R b These are independently selected from H and (C1-C4) alkyl groups; As defined and described in WO 2016 / 144849 and US 2018 / 0051035, each of these in whole is incorporated herein by reference.

[0177] In certain embodiments, the present invention relates to IRAK as an inhibitor of IRAK1 and IRAK4. [ka] And so, equation I-pp-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is, [ka] And here [ka] The symbol represents the part of this ring that is condensed with the pyrimidine ring, and the # represents -L 2 (R 4 ) P -R X And; R 1 and R 1’ Each of these is independent of -R 2 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; or 2 R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spiro-condensed, or bridged bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted; each R is independently hydrogen, or optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Each R 2 The group is optionally substituted, and is independently selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from Ci-6 aliphatic, phenyl, 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 4 These are independently halogens, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(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)2N(R)2, -N(R)S(O)2R, or optionally substituted groups, the optionally substituted groups being selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from C1-6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2; R z is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2; [Ar] is a 5- to 6-membered heteroaromatic ring having phenyl, or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where [Ar] is m examples of R 1 It has been replaced by; L 1 A is a covalent or C1-C6 divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; L 2 A is a covalent or C1-C6 divalent hydrocarbon chain, where one or two methylene units in the chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; m is between 0 and 4; n is 0 to 4; and p is between 0 and 2; As defined and described in WO 2017 / 004133, each of these in whole is incorporated herein by reference.

[0178] In certain embodiments, the present invention relates to IRAK as an inhibitor of IRAK1 and IRAK4. [ka] And so, equation I-qq-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Y is N or CR x and; Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1 and R v Each of these is independent of -R 2 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; or 2 R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spiro-condensed, or bridged bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Each R 2 The group is optionally substituted, and is independently selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from Ci-6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x and R y Each of them independently contains hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -H[Ar], -OR, or -S(O)2N(R)2; or R x and R y These atoms, together with the atoms between them, form a 4- to 7-membered partially unsaturated carbocyclic ring, or a partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2; [Ar] is a 5- to 6-membered heteroaromatic ring having phenyl, or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where this [Ar] is m examples of R r It has been replaced by; L 1 is a covalent or Ci-6 divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as necessary by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; m is 0 to 4; and n is between 0 and 4; As defined and described in WO 2017 / 004134, each of these in whole is incorporated herein by reference.

[0179] In certain embodiments, the present invention relates to an IRAK inhibitor. [ka] And so, formulas I-rr-1, I-rr-2, or I-rr-3: [ka] [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 These, together with the atoms to which they are bonded, form a heterocycline ring; R2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl, or aromatic aliphatic; Each R 3 These are independently H, aliphatic, halogen, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, aromatic aliphatic, -O-heterocyclyl, hydroxy, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate; y is between 1 and 6; Each of these terms, in whole, is defined and described in WO 2016 / 172560 and US 2016 / 0311839, which are incorporated herein by reference.

[0180] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-ss-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: A is [ka] and; X is N or CR 7 and; R is hydrogen, R 1 , halogen, cyano, nitro, -OR 1 -C(=O)-R 1 , -C(=O)OR 1 -C(=O)NR 11 -R 1 -S(=O)2-R 1 , -NR 11C(=O)-R 1 , -NR 11 C(=O)NR 11 R 11 , -NR 11 C(=O)OR 1 , -NR 11 S(=O)2R 1 or -NR 11 R 11 and; R 1 This is 0 to 4 R 1a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced by 2~6 Alkenyl, 0 to 3 R 1a C replaced by 2~6 Alkinyl, 0 to 3 R 1a C replaced by 3~10 Cycloalkyl, 0 to 3 R 1a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a A 5- to 10-membered heterocycle substituted with, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 1a It is a 5- to 10-membered heteroaryl substituted with; R 1a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) is replaced by r - It is a 5- to 7-membered heterocyclic ring or heteroaryl; R 2 This is 0 to 4 R 2a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 1 to 4 R 2a A 5- to 10-membered heterocycle, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 4 R atoms. 2a It is a 5- to 10-membered heteroaryl that is substituted with; R 2a In each of these entities, independently, hydrogen, =O, halo, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 2 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryl rings; R 3 This is 0 to 3 R 3a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced by 2~6 Alkenyl, 0 to 3 R 3a C replaced by 2~6 Alkinyl, 0 to 3 R 3a C replaced by 3~10 Cycloalkyl, 0 to 3 R 3a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3aA 5- to 10-membered heterocycline, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R atoms, which are substituted. 3a It is a 5- to 10-membered heteroaryl substituted with; R 3a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 1 R a -(CH2) replaced by r - It is a 5- to 7-membered heterocyclic ring or heteroaryl; R 4 and R 5 These are independently hydrogen atoms and 0 to 1 R atoms. f C replaced by 1~4 Alkyl, 0 to 3 R d (CH2)-phenyl substituted with, as well as carbon atoms, and N, O, and S(O) p Selected from -(CH2)- 5- to 7-membered heterocycles containing 1 to 4 heteroatoms; R 6 and R 7 In each of these entities, independently, hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c -S(O)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH2) replaced by r-3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryls, however, R 6 and R 7 Neither of them can become hydrogen; R 11 In each existence, hydrogen and R exist independently. e , 0 to 1 R f C replaced by 1~4 Alkyl, 0 to 3 R d CH2-phenyl, or carbon atoms substituted with, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R d It is a -(CH2)- 5-membered to 7-membered heterocycle that is substituted by; or R 11 And another R on the same nitrogen atom 11 , R 1 , or R 2 Together with these, they can form a complex ring with substitutions as needed; R a These are hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) r NR bC(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)2R c , 0 to 1 R f C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, -(CH2) r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p -(CH2) containing 1 to 4 heteroatoms selected from r -5- to 7-membered heterocyclic rings or heteroaryl rings; or two R atoms on adjacent or identical carbon atoms. a This is the formula -O-(CH2) n It forms a cyclic acetal of -O- or -O-CF2-O-, where n is selected from 1 or 2; R b is hydrogen, R e , 0 to 2 R d C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced by 3~6 Cycloalkyl, or 0 to 3 R d (CH2) replaced by r -It is phenyl; R c This is 0 to 1 R f C replaced by 1~6 Alkyl, C 3~6 Cycloalkyl, or 0 to 3 R f (CH2) replaced by r -It is phenyl; R d These are hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e ,-(CH2) r C(O)R c , -NRe R e , -NR e C(O)OR c , C 1~6 Alkyl, or 0 to 3 R f (CH2) replaced by r -It is phenyl; R e is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and 0 to 3 R f (CH2) replaced by r - Selected from phenyl; R f is hydrogen, halo, NH2, OH, or O(C) 1~6 Alkyl) is; p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; Each of these terms, in whole, is defined and described in WO 2013 / 106612 and US 2015 / 0011532, which are incorporated herein by reference.

[0181] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-tt-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: A is a triazole optionally substituted with 0 to 2 Rs; X is N or CR 7 and; R stands for hydrogen, R', halogen, cyano, nitro, -OR 1 -C(=O)-R 1 , -C(=O)OR1 -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)2R 1 or -NR 11 R 1 and; R 1 This is 0 to 4 R 1a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced by 2~6 Alkenyl, 0 to 3 R 1a C replaced by 2~6 Alkinyl, 0 to 3 R 1a C replaced by 3~10 Cycloalkyl, 0 to 3 R 1a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a A 5- to 10-membered heterocycle substituted with, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 1a It is a 5- to 10-membered heteroaryl substituted with; R 1a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) is replaced by r - It is a 5- to 7-membered heterocyclic ring or heteroaryl; R 2 This is 0 to 4 R 2a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 1 to 4 R 2a A 5- to 10-membered heterocycle, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 4 R atoms. 2a It is a 5- to 10-membered heteroaryl that is substituted with; R 2a In each of these entities, independently, hydrogen, =O, halo, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2)r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 2 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryl rings; R 3 This is 0 to 3 R 3a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced by 2~6 Alkenyl, 0 to 3 R 3a C replaced by 2~6 Alkinyl, 0 to 3 R 3a C replaced by 3~10 Cycloalkyl, 0 to 3 R 3a C replaced by 6~10It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3’ A 5- to 10-membered heterocycline, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R atoms, which are substituted. 3a It is a 5- to 10-membered heteroaryl substituted with; R 3a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 1 R a-(CH2) replaced by r - It is a 5- to 7-membered heterocyclic ring or heteroaryl; R 4 and R 5 These are independently hydrogen atoms and 0 to 1 R atoms. f C replaced by 1~4 Alkyl, 0 to 3 R d (CH2)-phenyl substituted with, as well as carbon atoms, and N, O, and S(O) p Selected from -(CH2)- 5- to 7-membered heterocycles containing 1 to 4 heteroatoms; R 6 and R 7 In each of these entities, independently, hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6Haloalkyl, 0 to 3 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryls, however, R 6 and R 7 Neither of them can become hydrogen; R 11 In each existence, hydrogen and R exist independently. e , 0 to 1 R f C replaced by 1~4 Alkyl, 0 to 3 R d CH2-phenyl, or carbon atom, substituted with N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R d It is a -(CH2)- 5-membered to 7-membered heterocycle that is substituted by; or R 11 And another R on the same nitrogen atom 11 , R 1 , or R 2 Together with these, they can form a complex ring with substitutions as needed; R a These are hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR bC(O)R c ,-(CH2) 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)2R c , 0 to 1 R f C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, -(CH2) r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p -(CH2) containing 1 to 4 heteroatoms selected from r -5- to 7-membered heterocyclic rings or heteroaryl rings; or two R atoms on adjacent or identical carbon atoms. a This is the formula -O-(CH2) n It forms a cyclic acetal of -O- or -O-CF2-O-, where n is selected from 1 or 2; R b is hydrogen, R e , 0 to 2 R d C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced by 3~6 Cycloalkyl, or 0 to 3 R d (CH2) replaced by r -It is phenyl; R c This is 0 to 1 R f C replaced by 1~6 Alkyl, C 3~6 Cycloalkyl, or 0 to 3 R f (CH2) replaced by r -It is phenyl; R d These are hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe ,-(CH2) 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 (CH2) replaced by r -It is phenyl; R e is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and 0 to 3 R f (CH2) replaced by r - Selected from phenyl; R f is hydrogen, halo, NH2, OH, or O(C) 1~6 Alkyl) is; p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; Each of these, in whole, is defined and described in WO 2013 / 106614 and US 2015 / 0045347, which are incorporated herein by reference.

[0182] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-uu-1: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is N or CR 7 and; R is R 1 , halogen, cyano, nitro, -OR 1 -C(=O)-R1 , -C(=O)OR 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)OR 1 , -NR 11 S(=O)2-R 1 , or -NR 11 -R 1 and; R 1 This is 0 to 4 R 1a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 1a C replaced by 2~6 Alkenyl, 0 to 3 R 1a C replaced by 2~6 Alkinyl, 0 to 3 R 1a C replaced by 3~10 Cycloalkyl, 0 to 3 R 1a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 1a It contains a 5- to 10-membered heterocycle substituted with , 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 1a It is a 5- to 10-membered heteroaryl substituted with; R 1a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) replaced by r -It is a complex algebra with 5 to 7 members; R 2 This is 0 to 4 R 2a C replaced by 6~10 It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 4 R 2a It contains 1 to 4 heteroatoms selected from N, O, and S, which are substituted with R, and 0 to 4 R 2a It is a 5- to 10-membered heteroaryl that is substituted with; R 2a In each of these entities, independently, hydrogen, =O, halo, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) rC(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 2 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryl rings; R 3 This is 0 to 3 R 3a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 3a C replaced by 2~6 Alkenyl, 0 to 3 R 3a C replaced by 2~6 Alkinyl, 0 to 3 R 3a C replaced by 3~10 Cycloalkyl, 0 to 3 R 3a C replaced by 6~10It contains 1 to 4 heteroatoms selected from aryl, N, O, and S, and 0 to 3 R 3a A 5- to 10-membered heterocycle substituted with, or containing 1 to 4 heteroatoms selected from N, O, and S, and 0 to 3 R 3a It is a 5- to 10-membered heteroaryl substituted with; R 3a These are hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 1 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 1 R a-(CH2) is replaced by r - It is a 5- to 7-membered heterocyclic ring or heteroaryl; R 4 and R 5 These are independently hydrogen atoms and 0 to 1 R atoms. f C replaced by 1~4 Alkyl, 0 to 3 R d (CH2)-phenyl substituted with, as well as carbon atoms, and N, O, and S(O) p Selected from -(CH2)- 5- to 7-membered heterocycles containing 1 to 4 heteroatoms; R 6 and R 7 In each of these entities, independently, hydrogen, =O, F, Cl, Br, OCF3, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11 ,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c , 0 to 2 R a C replaced by 1~6 Alkyl, C 1~6Haloalkyl, 0 to 3 R a -(CH2) replaced by r -3-membered to 14-membered carbon rings, or each being a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R a -(CH2) is replaced by r - Selected from 5-membered to 7-membered heterocyclic rings or heteroaryls, however, R 6 and R 7 Neither of them can become hydrogen; R 11 In each existence, R e , 0 to 1 R f C replaced by 1~4 Alkyl, 0 to 3 R d CH2-phenyl substituted with, or each of which is a carbon atom, as well as N, O, and S(O) p It contains 1 to 4 heteroatoms selected from and 0 to 3 R d It is a -(CH2)- 5- to 7-membered heterocyclic or heteroaryl compound that is substituted with; Alternatively, R 11 And another R on the same nitrogen atom 11 , R 1 , or R 2 Together with, as needed, substituted azetidinil, pyrrolidinil, piperidinil, morpholinil, or 4-(C 1~6 It may form alkyl)piperazinyl; R a R d , F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r Ure b ,-(CH2) r SR b ,-(CH2) r C(O)R b ,-(CH2) r C(O)OR b ,-(CH2) r OC(O)R b ,-(CH2) r NR 11 R 11,-(CH2) r C(O)NR 11 R 11 ,-(CH2) r NR b C(O)R c ,-(CH2) 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)2R c -S(O)2R c , 0 to 1 R f C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, -(CH2) r -3-membered to 14-membered carbon rings, or carbon atoms, as well as N, O, and S(O) p -(CH2) containing 1 to 4 heteroatoms selected from r -5- to 7-membered heterocycles; or two R atoms on adjacent or identical carbon atoms a This is the formula -O-(CH2) n It forms a cyclic acetal of -O- or -O-CF2-O-, where n is selected from 1 or 2; R b R c , 0 to 2 R d C replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C replaced by 3~6 Cycloalkyl, or 0 to 3 R d (CH2) replaced by r -It is phenyl; R c This is 0 to 1 R f C replaced by 1~6 Alkyl, C 3~6 Cycloalkyl, or 0 to 3 R f (CH2) replaced by r-It is phenyl; R d These are hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e ,-(CH2) 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 (CH2) replaced by r -It is phenyl; R e is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and 0 to 3 R f (CH2) replaced by r - Selected from phenyl; R f is hydrogen, halo, NH2, OH, or O(C) 1~6 Alkyl) is; p is 0, 1, or 2; r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; Each of these, in whole, is defined and described in WO 2013 / 106641 and US 2015 / 0018344, which are incorporated herein by reference.

[0183] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-vv-1 or I-vv-2: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: R 1 teeth, (a) 0 to 4 R 1a C replaced by 2~3 It is a hydroxyalkyl, where R 1a These are independently selected from F, Cl, -OH, -CHF2, -CN, -CF3, -OCH3, and cyclopropyl; (b) -O(C 1~3 Alkyl) and 0 to 4 R 1a C replaced by 1~3 It is alkyl, and here R 1a These are independently selected from F, Cl, -OH, -CHF2, -CN, -CF3, and cyclopropyl; (c) 0 to 7 R 1a C replaced by 4~8 It is alkyl, and here R 1a These are independently selected from F, Cl, -OH, -CHF2, -CF3, -CN-OCH3, cyclopropyl, and -OP(O)(OH)2; (d) -(CH2) 2~4 NHC(O)(C 1~6 Alkyl), -(CH2)2CH(CH3)NHC(O)(C 1~6 Alkyl), -(CH2)2CH(CH3)NHC(O)(CH2) 0~1 NH(C 1~6 Alkyl), or -(CH2)2CH(CH3)NHC(O)(CH2) 0~1 N(C 1~4 Alkyl)2; (e) -OH, -OCH3, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)NH2, -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)2CH3, -S(O)2NH2, -S(O)2(C 1~3 Alkyl), -S(C1~3 C(alkyl), thiazolyl, methylpyrazolyl, and C(-OH and cyclopropyl) substituted with 1~3 Cyclohexyls substituted with 0 to 2 substituents independently selected from alkyl groups; (f) -(CH2)2(phenyl), where this phenyl is -C(O)NH2, -C(O)NH(C 1~3 Alkyl) or substituted with -S(O)2NH2; or (g) -C(O)(C 1~3 Piperidinyl substituted with alkyl; and; R 2 These are phenyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazolyl, thiazolyl, or triazolyl, each being F, Cl, -OH, -CN, C 1~3 Alkyl, -CH2C(O)OCH3, -O(C 1~3 Alkyl), -NH2, -NH(C 1~3 Alkyl), -NH(cyclopropyl), -C(O)NH2, -NHC(O)(C 1~3 Substituting with 0 to 2 substituents independently selected from alkyl, -NH (tetrahydropyranyl), hydroxypyrrolidinyl, =O, -O (piperidinyl), and pyridinyl; and R 3 teeth, (a) F, -OH, -CH3, -CF3, and C 3~6 C substituted with 0 to 4 substituents independently selected from cycloalkyl groups 1~6 alkyl; (b) F, -OH, C 1~3 C substituted with 0 to 2 substituents independently selected from hydroxyalkyl, -CH3, -CF2H, -NH2, and -C(O)OCH2CH3 3~6 Cycloalkyl; (c) Oxetanil, tetrahydropyranil, or fluorotetrahydropyranil; (d) -OH, -CN, -O(C 1~3 Alkyl), C 1~3Hydroxyalkyl, -C(O)NH2, -S(O)2NH2, -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; Each of these, in whole, is defined and described in WO 2014 / 074675 and US 2015 / 0284382, which are incorporated herein by reference.

[0184] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-xx-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: R 1 This is an aromatic heterocyclic group which may be substituted as needed, or a C which may be substituted as needed. 6~14 It is an aryl group; R 2 is a hydrogen atom or substituent; R 3 and R 4 is independently a hydrogen atom or a substituent, or R 3 and R 4 They come together and form rings as needed, substituted as necessary; R 5 and R 6 is independently a hydrogen atom or a substituent, or R 5 and R 6 They come together and form rings as needed, substituted as necessary; X is CR 7 R 8 , NR 9 , O or S; R 7 and R 8 is independently a hydrogen atom or a substituent, or R 7 and R 8 They come together and form a ring as needed, substituted as necessary; and R 9 is a hydrogen atom or substituent; Each of these, in whole, is defined and described in WO 2015 / 068856 and US 2015 / 0133451, which are incorporated herein by reference.

[0185] In certain embodiments, the present invention relates to an LBM that binds to E3 ubiquitin ligase (IAP). [ka] Therefore, equation I-yy-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and the variable R is as defined and described in Ohoka, N. et al. (2017). In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs). Journal of Biological Chemistry, 292(11), 4556-4570, each of which is incorporated herein by reference.

[0186] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-zz-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: R 1 This represents non-existence, A or Q-Het, Z is [ka] And here X represents O, S, or N. Y represents either C or N. T represents C or N, or Z represents a pyridine group or pyridazine group. R a It does not exist, OR 3 , CF3, Hal, or NO2, R b It does not exist, or it is A, or COHet. R 2 This represents H, Het, Q-Het, Cyc, A, or OA. Each Het is independently a 4- to 9-membered monocyclic ring, or a condensed, spiro, or bridging bicyclic ring, which is saturated, unsaturated, or aromatic, and which contains 1 to 3 heteroatoms independently selected from N, O, and S, as well as the group CO, SO, or SO2, where 1 or 2 H atoms are A, OA, COA, CN, Hal, NO2, OR 3 , can be replaced by SOA and / or SO2A, Cyc contains the base SO, SO2, or CO as needed, and CO(NR 3 )2, COHet, OR 3 , Het 1 ,A,CH2Het 1NH2, NHCOA, OCH2Cyc 1 , represents a 4-8 saturated carbocyclic ring, optionally substituted once or twice with a group selected from SO2A and -SA(=NH)(=O), Each Q is independently a linear or branched alkylene having 1 to 6 carbon atoms, where 1 to 5 H atoms are OR 3 , Hal, and N(R 3 )2 can be replaced by a group independently selected from 2, and one or two CH2 groups may be CO, SO, SO2 and NR 3 It can be replaced by a group independently selected from or represents a 4- to 8-membered divalent heterocyclic ring that is saturated, unsaturated, or aromatic and contains 1 to 3 heteroatoms independently selected from N, O, and S. Each A is independently a linear or branched alkyl group having 1 to 10 carbon atoms, where 1 to 7 H atoms are -OR 3 , Hal, NHSO2A, SO2A, SOA, and N(R 3 ) can be replaced by a group independently selected from 2, and one, two or three non-adjacent -CH2- groups can be replaced by -CO-, NR 3 and can be replaced by a group independently selected from -O-, Each Hal is independently F, Cl, Br, or I. Each R 3 These are independently H or C1-C6-alkyl, where one H atom may be replaced by a group selected from OH, O-C1-C6-alkyl, and Hal. Each Het 1 It is independently a five- or six-membered saturated monocyclic heterocycle containing one to three N atoms and / or O atoms, which are optionally monosubstituted by A. Cyc 1 This represents a cycloalkyl group having 3 to 7 atoms; each of these wholes is defined and described in WO 2014 / 008992 and US 2015 / 0141396, which are incorporated herein by reference.

[0187] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-aaa-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is a monocyclic heteroaryl; R 1 This is 1 to 3 R 10 It is a monocyclic or bicyclic heteroaryl that is substituted as needed; R 2 -C(O)NH2, -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 (Pyrazolyl as substituted as necessary), -C(O)-R 0 -C(O)-cycloalkyl, -S(O)2NH2, -S(O)2NH-R 0 -S(O)2NH-cycloalkyl, -R 00 -OH, -R 00 -OR 0 ,-R 00 -(morpholine-4-yl)phenyl, oxadiazolyl, or tetrazolyl, R 0 And it is replaced as needed, and here R 2 The oxadiazolyl inside is R 0 , R 00 -OH or R 0 -OR 0 It can be replaced by; R 3 H, R 0, halogens, 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 And here 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 -(morpholine-4-yl), -R 00 -OH, -R 00 -OR 0 , morpholine-4-yl, or -R 00 -(morpholine-4-yl) may be substituted; R 10 They may be the same or different from each other, R 0 , halogens, lower alkyl or haloalkyl, cycloalkyl, -OR 0 , optionally substituted amino, -O-lower alkyl or haloalkyl, -R 00 -OH, -R 00 -OR 0 is or -R 00 - is amino-substituted as needed, R 0 They are lower alkyl groups, either the same as or different from each other; R 00 These are either identical or different from one another, and these are lower alkylenes; The whole is as defined and described in WO 2011 / 043371, which is incorporated herein by reference.

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

[0189] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-bbb-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is selected from O, S, and NH; A is selected from aryl or heteroaryl; R is independently hydrogen, cyano, halo, hydroxy, -N02, and -NR in each of these entities. 3 R 4 , optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl; where the substituents as needed are independently, in the presence of each, halo, alkyl, haloalkyl, cyano, -NR 5 R 6 or -COOR 7 Selected from; R1 In each presence, is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; where cycloalkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and arylalkyl may be substituted as needed with hydroxy, alkyl, haloalkyl, cyano or halo; Y is a direct bond, O, -C(O)-, or NR 7 Selected from; R 2 In each of these entities, independently, hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl, -S0 2 R 5 or selected from oxo; R 3 and R 4 The substituents are independently selected from hydrogen, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted aryl; where the substituents are independently selected in each presence from halo, haloalkyl, or -COOR 7 Selected from; R 5 and R 6 These are independently hydrogen, alkyl, and COR 7 or -COOR 7 Selected from; R 7 In each instance, it is independently selected from hydrogen or alkyl; and m, n, and p are selected from 1, 2, or 3; The whole is as defined and described in WO 2013 / 042137, which is incorporated herein by reference.

[0190] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, formula I-ccc-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring Z1 is a heteroaryl that is substituted as needed; Ring Z2 is optionally substituted heterocycloalkyl, optionally substituted heteroaryl, or a direct bond; R1 is alkyl, cyano, -NR a R b or optionally substituted groups, the optionally substituted groups being selected from cycloalkyl, aryl, or heterocyclyl groups; where the substituents are, independently in each presence, alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2; R2 is an optionally substituted group, independently selected from alkyl or cycloalkyl groups in each presence; where the substituent is independently a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy in each presence; R3 independently comprises hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, and -NR in each of its forms. a R b , hydroxyl or hydroxyalkyl; R a is hydrogen or alkyl; R b These are hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; m and n are independently 1 or 2; Each of these terms, in whole, is defined and described in WO 2015 / 104662 and US 2016 / 0326151, which are incorporated herein by reference.

[0191] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-ddd-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X1 and X3 are independently CH or N; X2 is CR2 or N; however, only one of X1, X2, or X3 is N; A is either O or S; Y is either -CH2- or O; Ring Z is an aryl or heterocyclyl; R1 is, independently in each presence, a halo or optionally substituted heterocycline; where the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NR a R b and; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b Here, the substituent is alkyl, amino, halo, or hydroxyl; R3 is either alkyl or hydroxyl in each instance; R a and R b These are independently hydrogen, alkyl, acyl, or heterocyclyl; m and n are independently 0, 1, or 2; p is either 0 or 1; Each of these terms, in whole, is defined and described in WO 2015 / 104688 and US 2016 / 0340366, which are incorporated herein by reference.

[0192] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, formula I-eee-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Z1 is a cycloalkyl, aryl, or heterocyclyl as needed, or is absent; Z2 is a cycloalkyl, aryl, or heterocycline, as needed; R1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R2 is, in each presence, hydrogen, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R3 is, in each presence, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NR a R b and; Ra and R b Each element is, independently of the others, hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; m is 0, 1, or 2 in each existence; and n is 0, 1, or 2 in each existence; Each of these terms, in whole, is defined and described in WO 2015 / 193846 and US 2017 / 0152263, which are incorporated herein by reference.

[0193] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I - fff - 1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and R 0 represents hydrogen or C1-C4-alkyl, where this C1-C4-alkyl radical may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of hydroxyl and halogens; R 1 These are hydrogen, halogen, cyano, C(=O)OH, and C(=O)OR. a , C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , C(=O)R d , represents hydroxy or C1-C6-alkyl, where this C1-C6-alkyl radical is hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa S(=O)2-C1~C6-alkyl, NH2, NHR a , N(R a )R b , C1-C6 alkoxys that are monosubstituted or polysubstituted as necessary by the same or different radicals from the group consisting of halogens, C3-C8 cycloalkoxys that are monosubstituted or polysubstituted as necessary by the same or different radicals from the group consisting of halogens, R c Heterocycloalkyls are monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of the same or different radicals, Alternatively, it represents C1-C6 alkoxy, where this C1-C6 alkoxy radical is hydroxyl, halogen, cyano, C(=O)OH, C(=O)OR a S(=O)2-C1~C6-alkyl, NH2, NHR a , N(R a )R b , C3-C8 cycloalkyls optionally monosubstituted or polysubstituted by the same or different radicals from the halogen group, C1-C6 alkoxys optionally monosubstituted or polysubstituted by the same or different radicals from the halogen group, C3-C8 cycloalkoxys optionally monosubstituted or polysubstituted by the same or different radicals from the halogen group, R c Heterocycloalkyls, R, which are monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of the same or different radicals. c An aryl or R that is monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of the same or different radicals. c Can five-membered or six-membered heteroaryls be monosubstituted or polysubstituted as necessary by identical or different radicals from the group consisting of identical or different radicals from the group consisting of identical or different radicals, Alternatively, it represents a C3-C8 cycloalkoxy or heterocycloalkoxy, which may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl. Alternatively, it represents an aryloxy or a 5-membered or 6-membered heteroaryloxy, where alkoxy and 5-membered or 6-membered heteroaryloxy are hydroxy, halogen, cyano, C(=O)OH, C(=O)OR a It can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C6 alkyl and C1-C6 alkoxy compounds. Alternatively, it represents a C3-C8 cycloalkyl or heterocycloalkyl group, which may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl groups. Alternatively, it may represent a C2-C6 alkenyl or C2-C6 alkynyl. Alternatively, aryl, 5- to 10-membered heteroaryl, aryl-C1-C4-alkyl, or 5- or 6-membered heteroaryl-C1-C4-alkyl, where aryl and heteroaryl are halogen, hydroxyl, cyano, C(=O)OH, C(=O)OR a They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkoxy; R a These are C1-C6 alkyl and C3-C 10 -Represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of halogen, hydroxy, cyano, C1-C3-alkyl, C1-C3-alkoxy, heterocycloalkyl, -C(=O)O-C1-C6-alkyl, and S(=O)2-C1-C6-alkyl; R bC1-C6 alkyl or C3-C 10 - Does it represent a cycloalkyl group? Or R a and R b It combines with a nitrogen atom to form a five- or six-membered heterocycle, which may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6-alkyl groups; R c is a hydroxyl, halogen, cyano, C1-C3 alkyl, or C1-C3 alkoxy; R d This includes hydrogen, C1-C6 alkyl or C3-C 10 - Represents cycloalkyl; R 2 ' represents hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 13 represents hydrogen or C1-C6 alkyl; W contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and R 3 This may be substituted as needed, and the same or different radicals R 4 This represents a 5-membered heteroaryl that can be monosubstituted or polysubstituted as needed, W is R 3 This may be substituted as needed, and the same or different radicals R 4 This represents pyridyl, pyrazinyl, pyridadinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl, which may be monosubstituted or polysubstituted as needed; R 3 These are hydrogen, halogens, cyanosides, and C(=O)R. a NH2, NHR a , N(R a )R b , N(H)C(=O)R a Or it represents C1-C6 alkyl, Here, C1-C6 alkyl refers to hydroxyl, halogen, cyano, and C(=O)R. a C(=O)OH, C(=O)OR aS(=O)2-C1~C6-alkyl, NH2, NHR a , N(R a )R b It may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C6 alkoxys and C3-C8 cycloalkoxys. Here, can C1-C6 alkoxys and C3-C8 cycloalkoxys be monosubstituted or polysubstituted as needed by the same or different halogen radicals? Alternatively, the C1-C6 alkyl group is monosubstituted or polysubstituted as needed by the same or radical group from the group consisting of C3-C6 cycloalkyl and heterocycloalkyl groups. Here, C3-C6 cycloalkyl and heterocycloalkyl groups may be monosubstituted, disubstituted, or trisubstituted as needed by the same or different radicals from the group consisting of halogens, cyano, C1-C3 alkyl, and C1-C3 alkoxy groups. Alternatively, the C1-C6 alkyl group may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of aryl and 5-membered or 6-membered heteroaryl groups. Here, aryls and 5-membered or 6-membered heteroaryls may be monosubstituted, disubstituted, or trisubstituted as needed by the same or different radicals from the group consisting of halogens, cyanos, C1-C3-alkyls, and C1-C3-alkoxys. Or R 3 This represents C1-C6 alkoxy, Here, C1-C6-alkoxy are hydroxyl, halogen, cyano, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b It can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C3-C8 cycloalkyl, C1-C4 alkoxy, and C3-C8 cycloalkoxy. Alternatively, C3-C6 cycloalkyl, heterocycloalkyl, or C5-C 11- Represents spirocycloalkyl, where cycloalkyl, heterocycloalkyl and spirocycloalkyl are hydroxy, halogen, cyano, C(=O)R a C(=O)OH, C(=O)OR a Can it be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C6 alkyl and C1-C4 alkoxy? Alternatively, it represents an aryl or a 5- to 10-membered heteroaryl. Here, aryl and heteroaryl are halogen, hydroxy, cyano, and C(=O)OR a S(=O)2-C1~C6-alkyl, NO2, NH2, NHR a , N(R a )R b , N(H)C(=O)R a The molecules may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C3-C8 cycloalkyl, C1-C3 alkoxy, and C1-C3 alkyl, where C1-C3 alkyl groups may be monosubstituted or polysubstituted as needed with the same or different halogen radicals; R 4 represents halogen, hydroxyl, cyano or C1-C6-alkyl, where C1-C6-alkyl refers to halogen, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, and C3-C 10 -C1-C6 alkoxys may be monosubstituted or polysubstituted as necessary by the same or different radicals from the group consisting of cycloalkyls, 3- to 10-membered heterocycloalkyls, and aryls, where C1-C6 alkoxys may be monosubstituted or polysubstituted as necessary by the same or different radicals from the group consisting of halogens, where aryls may be monosubstituted or polysubstituted as necessary by the same or different radicals R; Or R 4 This represents an aryl or heteroaryl that can be monosubstituted or polysubstituted as needed by the same or different radicals R; Or R 4 C(=O)R a, C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , C(=O)OR a NH2, NHR a , N(R a )R b , N(H)C(=O)R a , N(R a )C(=O)R a , N(H)C(=O)NH2, N(H)C(=O)NHR a , N(H)C(=O)N(R a )R b , N(R a )C(=O)NH2, 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 NO2, N(H)S(=O)R a , N(R a )S(=O)R a N(H)S(=O)2R a , N(R a )S(=O)2R a N=S(=O)(R a )R b ,OC(=O)R a OC(=O)NH2, OC(=O)NHR a ,OC(=O)N(R a )R b SH, SR a , S(=O)R a , S(=O)2R a , S(=O)2NH2, S(=O)2NHR a , S(=O)2N(R a )R b Or S(=O)(=NR a )R b It represents; R is a halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10-Cycloalkyl, 3-membered to 10-membered heterocycloalkyl, aryl, heteroaryl, C(=O)R a , C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , C(=O)OR a NH2, NHR a , N(R a )R b , N(H)C(=O)R a , N(R a )C(=O)R a , N(H)C(=O)NH2, N(H)C(=O)NHR a , N(H)C(=O)N(R a )R b , N(R a )C(=O)NH2, 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 NO2, N(H)S(=O)R a , N(R a )S(=O)R a N(H)S(=O)2R a , N(R a )S(=O)2R a N=S(=O)(R a )R b OH, C1~C6-alkoxy, OC(=O)R a OC(=O)NH2, OC(=O)NHR a ,OC(=O)N(R a )R b SH, SR a , S(=O)R a , S(=O)2R a , S(=O)2NH2, S(=O)2NHR a , S(=O)2N(R a )R b Or S(=O)(=NR a )R b It represents; n represents either 0 or 1; Y is: [ka] This represents a group selected from the list, where * represents the bond site of this group to the rest of the molecule; R 5 This includes hydrogen, C1-C6 alkyl or C3-C 10 - Represents cycloalkyl, where C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxys and C3-C8 cycloalkyls; R 6 Here, represents hydrogen or C1-C6 alkyl, C1-C6 alkyl groups are hydroxyl, halogen, cyano, and C3-C 10 -Cycloalkyl, C(=O)R a C(=O)OH, C(=O)OR a , S(=O)2-C1~C6-alkyl, N(R a )R b , can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxys and C3-C8 cycloalkoxys, or C3-C 10 - Represents cycloalkyl, where C3~C 10 -Cycloalkyls may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6-alkyl groups, where C1-C6 alkyls may be substituted with hydroxyls as needed, or represent heterocycloalkyls, where Heterocycloalkyls can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of halogens, cyanos, C1-C3-alkyls, and C1-C3-alkoxys, or they represent aryls or 5-membered or 6-membered heteroaryls, where Aryls and 5-membered or 6-membered heteroaryls include halogens, cyanos, C1-C3-alkyls, C1-C3-alkoxys, S(=O)2NH2, and S(=O)2NHR. a and S(=O)2N(R a )R b They may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of; R 7a Hydrogen, halogen, N(R) a )R b , C1~C6-alkyl or C3~C 10 -Represents cycloalkyl, where C1-C6-alkyl can be hydroxy, halogen, cyano, C(=O)OH, or C(=O)OR a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; R 7b The '' represents hydrogen, halogen, or C1-C6-alkyl, where C1-C6-alkyl is hydroxy, halogen, cyano, C(=O)OH, or C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; Or R 7a and R 7bThese atoms, together with carbon atoms, form C3-C6 cycloalkyl groups, which can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl groups. Or R 7a and R 7b Together, they represent the oxo group; R 7c Hydrogen, halogen, N(R) a )R b , C1~C6-alkyl or C3~C 10 - Represents cycloalkyl, where C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; R 7d Here, represents hydrogen, halogen, or C1-C6 alkyl, and C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; Or R 7c and R 7d These atoms, together with carbon atoms, form C3-C6 cycloalkyl groups, which can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl groups. Or R 7c and R 7d Together, they represent the oxo group; R 8a Hydrogen, halogen, N(R)a )R b , C1~C6-alkyl or C3~C 10 - Represents cycloalkyl, where C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; R 8b Here, represents hydrogen, halogen, or C1-C6 alkyl, and C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; Or R 8a and R 8b These atoms, together with carbon atoms, form C3-C6 cycloalkyl groups, which can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl groups. R 8c Hydrogen, halogen, N(R) a )R b , C1~C6-alkyl or C3~C 10 - Represents cycloalkyl, where C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; R 8d Here, represents hydrogen, halogen, or C1-C6 alkyl, and C1-C6 alkyl groups are hydroxy, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b They may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of C1-C4 alkoxy, C3-C8 cycloalkyl, and heterocycloalkyl; Or R 8c and R 8d These atoms, together with carbon atoms, form C3-C6 cycloalkyl groups, which can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxy, halogen, cyano, and C1-C6 alkyl groups. Or R 8c and R 8d Together, they represent the 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 cannot simultaneously represent 0; Z is C (=O), CR 9 R 10 , NR 11 , represents a group selected from O, S, S(=O), and S(=O)2; R 9 This represents hydrogen or C1-C6 alkyl. R 10 These are hydrogen, halogens, cyanosides, and C(=O)R. a C(=O)OH, C(=O)OR a , C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , N(H)C(=O)R a , N(R b )C(=O)Ra , S(=O)2R a , hydroxy, N(R a )R b And represents C1-C6 alkyl, where C1-C6 alkyl groups are hydroxyl, halogen, cyano, and C(=O)R. a C(=O)OH, C(=O)OR a , S(=O)2-C1~C6-alkyl, N(R a )R b , can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C4 alkoxys and C3-C8 cycloalkoxys, or represent C1-C6 alkoxy, where C1-C6-alkoxy groups include hydroxyl, halogen, cyano, C(=O)OH, and C(=O)OR. a , S(=O)2-C1~C6-alkyl, N(R a )R b The molecules may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C3-C8 cycloalkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, heterocycloalkyl, aryl, and 5-membered or 6-membered heteroaryl, where Aryls and 5-membered or 6-membered heteroaryls may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of halogens, cyanos, C1-C3-alkyls and C1-C3-alkoxys, or represent aryloxys or 5-membered or 6-membered heteroaryloxys, where aryloxys and 5-membered or 6-membered heteroaryloxys are hydroxy, halogens, cyanos, C(=O)OH, C(=O)OR a It can be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C3 alkyl and C1-C3 alkoxy compounds. Alternatively, it represents C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, heterocycloalkyl, or heterocycloalkyl-C1-C4-alkyl, which are hydroxy, halogen, cyano, and C(=O)R. aC(=O)OH, C(=O)OR a The molecules may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C6 alkyl and C1-C6 alkoxy molecules, where Can C1-C6 alkoxy groups be monosubstituted or polysubstituted as needed with the same or different halogen radicals or oxo groups? Alternatively, it may represent a C2-C6 alkenyl or C2-C6 alkynyl. Alternatively, it represents an aryl, a 5- to 10-membered heteroaryl, an aryl-C1 to C4-alkyl, or a 5- or 6-membered heteroaryl-C1 to C4-alkyl, where Aryl and heteroaryl compounds include halogens, hydroxyls, cyanos, C(=O)OH, and C(=O)OR. a NHR a , N(R a )R b It may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of C1-C3-alkyl, C3-C8-cycloalkyl, and C1-C3-alkoxy; Or R 9 and R 10 It combines with a carbon atom to form a C3-C8 cycloalkyl or 4-membered-6-membered heterocycle, where This C3-C8 cycloalkyl radical or this 4- to 6-membered heterocycle is a hydroxyl, halogen, cyano, C1-C6 alkyl, C(=O)R a and may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of oxo groups; R 11 is hydrogen, C(=O)R a , C(=O)OR a , C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , S(=O)2R a , S(=O)2N(R a )R b Or it represents C1-C6 alkyl, where C1-C6 alkyl groups are hydroxyl, halogen, cyano, and C(=O)R. a , C(=O)OR a , C(=O)NH2, C(=O)N(H)R a , C(=O)N(R a )R b , S(=O)2-C1~C6-alkyl, N(R a )R b The molecules may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C3-C8 cycloalkyl, C1-C4 alkoxy, and C3-C8 cycloalkoxy, where Can C3-C8 cycloalkyl, C1-C4 alkoxy, and C3-C8 cycloalkoxy molecules be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of hydroxyl and halogens? Alternatively, it represents a C3-C8 cycloalkyl, heterocycloalkyl, or heterocycloalkyl-C1-C4 alkyl, which may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of hydroxy, halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy, where alkyl and alkoxy may be monosubstituted or polysubstituted as needed by the same or different radicals from the group consisting of halogen and oxo groups. Alternatively, it may represent a C2-C6 alkenyl or C2-C6 alkynyl. Alternatively, it represents an aryl, a 5- to 10-membered heteroaryl, an aryl-C1 to C4-alkyl, or a 5- or 6-membered heteroaryl-C1 to C4-alkyl, where Aryl and heteroaryl compounds include halogens, hydroxyls, cyanos, C(=O)OH, and C(=O)OR. a They may be monosubstituted or polysubstituted as needed with the same or different radicals from the group consisting of C1-C3-alkyl, C3-C8-cycloalkyl, and C1-C3-alkoxy; Each of these, in whole, is defined and described in WO 2015 / 091426 and US 2016 / 0311833, which are incorporated herein by reference.

[0194] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I - ggg - 1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Ring A is a phenylene or a 5- to 6-membered heteroarylene containing 1 to 3 heteroatoms selected from O, S, and N, where ring A is optionally substituted with further substituted lower alkyl groups as needed. Ring B is a 5- to 6-membered heterocycloalkylene containing 1 to 3 heteroatoms selected from phenylene, O, S, and N, or a 5- to 6-membered heteroarylene containing 1 to 3 heteroatoms selected from O, S, and N, where ring B is optionally substituted with further substituted lower alkyl groups as needed. R 3 This is selected from hydrogen, lower alkyl groups, and lower alkyl, heterocycloalkyl, and heteroaryl groups, which are optionally substituted with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, or phenyl. Here, phenyl, heterocycloalkyl, and heteroaryl groups are optionally substituted with one or two groups independently selected from lower alkyl groups, and alkoxy groups are optionally substituted with tri(alkyl)silyl groups. R 4 These are selected from heteroarylenes and arylenes, each of which is substituted as needed, or R 4 and R 3 These, together with the nitrogen to which they are bonded, form a substituted 3- to 7-membered heterocycloalkyl ring as needed, or R4 This is an alkylene chain having 1 to 3 carbon atoms, optionally substituted with one or two groups independently selected from lower alkyl and cycloalkyl groups, each of which is optionally substituted with a hydroxyl or alkoxy group, or R 4 It does not exist. R 5 C(O)NR 51 , NR 52 , and O are selected, or R 5 It does not exist, however, R 4 If R does not exist, 5 It does not exist. R 6 This is an alkylene chain, or an alkenylene chain having one or two double bonds. Here, this alkylene chain or alkenylene chain has 2 to 10 carbon atoms, Here, this alkylene or alkenylene chain is optionally substituted with one or two groups independently selected from lower alkyl and cycloalkyl groups, each of which is optionally substituted with a hydroxyl or alkoxy group, and Furthermore, one or two of the carbon atoms in this alkylene chain may be O, S, SO, SO2, or NR. 61 It is replaced as needed, and Here, two of the carbon atoms in this alkylene chain are connected as needed by an alkylene chain of two or three carbon atoms to form a 5- to 7-membered ring. R 7 , NR 71 And selected from O or R 7 It does not exist. R 51 These are selected from hydrogen and lower alkyl groups. R 52 These are hydrogen, lower alkyl, and -C(O)OR 81 Selected from, R 61 These are hydrogen, lower alkyl, and -C(O)OR 81 Selected from, R 71 These are hydrogen, lower alkyl, and -C(O)OR 81 Selected from, and R 81 It is a lower alkyl group; Each of these terms, in whole, is defined and described in WO 2014 / 143672 and US 2016 / 0002265, which are incorporated herein by reference.

[0195] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-hhh-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[1,2-b]pyridazine, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, where this heteroaryl is R a and R b It has been replaced with; R a These are H, F, Cl, Br, -CN, -OH, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, -NH2, -NH(C 1~4 Alkyl), -N(C 1~4 Alkyl)2,-NH(C 1~4 Hydroxyalkyl), -NH(C 1~4 Fluoroalkyl), -NH(C 1~6Hydroxyfluoroalkyl), -C(O)NH2, -CH2NHC(O)(C 1~6 Alkyl), -CH2NHC(O)(C 1~6 Hydroxyalkyl), -CH2NHC(O)NH(C 1~6 Alkyl), -CH2NHC(O)NHCH2(phenyl), -CH2NHC(O)N(C 1~4 Alkyl)2,-CH2NHC(O)O(C 1~4 Alkyl), -CH2NHC(O)(C 3~6 Cycloalkyl), -CH2NHC(O)(tetrahydrofuranyl), -CH2NHC(O)CH2(C 3~6 Cycloalkyl), -CH2NHC(O)CH2(tetrahydropyranyl), -CH2NHC(O)CH2(phenyl), -NHC(O)(C 1~4 It is alkyl, pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl; R b is H or -NH2; R1 is (I C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Hydroxyalkyl, C 1~8 Hydroxyfluoroalkyl, -(C 1~6 Alkyrenyl)O(C 1~4 Alkyl), -(C 1~6 Alkyrenyl)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 Alkyrenyl) NHC(O)(C 1~4 Alkyrenyl)OC(O)(C 1~3 Alkyl), -(C 1~6 Alkyrenyl) NHS(O)2(C1~4 Alkyl), -(C 1~6 Alkyrenyl)P(O)(C 1~4 Alkoxy)2, -(C 1~6 Fluoroalkenyl)NH(C 1~4 Alkyl), -(C 1~6 Alkyrenyl)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 (Alkirenyl)R x ,-(C 1~3 Fluoroalkenyl)R x ,-(C 1~3 Alkirenyl)C(O)R x ,-(C 1~3 Alkyrenyl)C(O)NHR x ,-(C 1~3 Fluoroalkenyl)C(O)R x , or -CH2CF=(tetrahydropyranyl), where R x C 3~6 A cyclic group selected from cycloalkyl, tetrazolyl, 1,1-dioxidetetrahydrothiophenyl, 1,1-dioxidethiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl, and triazinyl, where each cyclic group is substituted with 0 to 3 substituents independently selected from F, -OH, -CH3, -C(CH2)2OH, -OCH3, -C(O)CH2CN, -S(O)2CH3, -S(O)2NH2, -NHC(O)CH3, -N(S(O)2CH3)2, -CH2CH2(acetamidophenyl), -CH2CH2(methoxyphenyl), -CH2CH2(sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl; (iii) C3~6 Cycloalkyl or C 4~6 A cycloalkenyl, where each is F, -OH, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, -S(C 1~3 Alkyl), -NO2, -S(O)2(C 1~3 Alkyl), C 1~4 Hydroxyalkyl, -C(C 1~3 Alkyl)(OH)(C 3~6 Cycloalkyl), -CH2C(O)NH(C 1~3 Alkyl), -NHC(O)(C 1~3 Alkyl), -NHC(O)(C 1~4 Hydroxyalkyl), -C(O)NH(C 1~3 Alkyl), -C(O)NH(C 1~3 Deuteroalkyl), -C(O)NH(C 3~6 Cycloalkyl), -NHC(O)O(C 1~3 Alkyl), -NHS(O)2(C 1~3 Substituted with 0 to 3 substituents independently selected from alkyl, pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl; (iv) Tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each containing -OH, C 1~3 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, C 1~3 Alkoxy, -C(O)(C 1~4 Alkyl), -S(O)2(C 1~4 Alkyl), -S(O)2NH(C 1~4 Alkyl), -NH(C 1~3 Alkyl), -N(C 1~3 Alkyl)2,-O(C 1~3 Alkyrenyl)N(C 1~3Substituted with 0 to 1 substituent selected from alkyl)2, -CH2(morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperadinyl, piperidinyl, methylpiperazinyl, methoxypiperazinyl, pyridinyl, pyrimidinyl, methylsulfonylazetidinyl, and -C(O)(methylsulfonylazetidinyl); or (v) Pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol, tetrahydrobenzo[d]thiazole-2-amine, or 1,3-diazaspiro[4.5]decane-2,4-dione and R2 is (I C 1~7 Alkyl or C 2~6 Alkenyls, each substituted with 0 to 3 substituents independently selected from F, -OH, and -CN;-(C 1~4 Alkyrenyl)O(C 1~4 Alkyl), -(C 1~4 Alkyrenyl)O(C 1~4 Fluoroalkyl), -(C 1~6 Alkyrenyl)NH2,-(C 1~6 Alkyrenyl)S(O)2(C 1~3 Alkyl), -(C 1~6 Fluoroalkenyl)NH(C 1~3 Alkyl), or -(C 1~6 Alkyrenyl) NHC(O)(C 1~4 Fluoroalkyl); (ii) -(C 1~4 (Alkirenyl)R y And here R y C 3~6 These are cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each consisting of F, -OH, and C 1~3 Substituting with 0 to 2 substituents independently selected from the alkyl group; (iii) C 3~6Cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each comprising F, -OH, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, -C(O)(C 1~3 Alkyl), -C(O)(C 1~3 Fluoroalkyl), -C(O)(C 1~3 Cyanoalkyl), -C(O)O(C 1~3 Alkyl), -C(O)NH2, -C(O)NH(C 1~3 Alkyl), -C(O)(difluorophenyl), -NH2, -NH(C 1~3 Alkyl), -NH(C 1~3 Fluoroalkyl), -NH(oxetanyl), -NHC(O)(C 1~3 Alkyl), -NHC(O)(C 1~3 Fluoroalkyl), -NHC(O)(C 3~6 Cycloalkyl), -NHC(O)(fluorophenyl), -S(O)2(C 1~3 Substituted with 0 to 3 substituents independently selected from alkyl, imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and methoxypyrimidinyl; (iv) Adamantanil, hydroxyadamantanil, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl, bicyclo[1.1.1]pentanil, or hydroxy-bicyclo[2.2.1]heptanil; or (v) Phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or indazolyl, each being 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 Alkyrenyl)O(C 1~3 Alkyl), -(C 1~3 Alkyrenyl)O(C 1~3Fluoroalkyl), -C(O)NH2, -C(O)NH(C 1~3 Alkyl), -NHC(O)(C 1~3 Alkyl), -NHC(O)S(O)2(C 1~3 Alkyl), -S(O)2NH2, -S(O)2(C 1~3 Substituted with 0 to 2 substituents independently selected from alkyl, pyrazolyl, methylpyrazolyl, imidazolyl, triazolyl, methyltetrazolyl, ethyltetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and tetrahydropyranyl. and; Each of these, in whole, is defined and described in WO 2015 / 103453 and US 2015 / 0191464, which are incorporated herein by reference.

[0196] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-iii-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and [ka] It is either a single bond or a double bond; W stands for CH, CH-CH, O, S, NR 6 Selected from , and CO; Y is N or CR 9 and; Z is N or C, W is CH, and Y is CR 9 If that is the case, then Z is N; R 4 is hydrogen, halogen, OR 6 , CN, NR 7 R8 CH2OR 6 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic ring, optionally substituted carbocyclic, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, CO2R 6 SO3R 6 SO2R 6 and SO2NR 7 R 8 Selected from; R 5 is hydrogen, halogen, OR 6 Selected from, as necessary, substituted C1-C6 alkyls, as necessary, substituted C1-C6 haloalkyls, as necessary, substituted C1-C6 heteroalkyls, as necessary, substituted C1-C6 haloheteroalkyls, as necessary, substituted C1-C6 alkenyls, and as necessary, substituted C1-C6 alkynyls; or R 4 and R 5 They combine to form non-aromatic rings, which may be substituted as needed; Each R 6 Each is independently condensed as necessary with a substituted aryl or substituted heteroaryl, as necessary, as an optionally substituted aryl, as necessary substituted heteroaryl, and as necessary substituted non-aromatic rings, hydrogen, and as necessary substituted C1-C 10 Alkyl, and C1-C as needed. 10 Haloalkyl groups and, if necessary, substituted C1-C groups. 10 Selected from heteroalkyl groups; R 7 and R 8 Each of these independently consists of an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic ring, hydrogen, optionally substituted C1-C, each optionally condensed with a substituted aryl or substituted heteroaryl. 10Alkyl, and C1-C as needed. 10 Haloalkyl, C1-C as needed, substituted as necessary. 10 Alkenyl, substituted C1-C as needed 10 Alkynyl and, if necessary, substituted C1-C 10 Selected from heteroalkyl groups, or R 7 and R 8 They combine to form non-aromatic rings, which may be substituted as needed; R 9 is hydrogen, halogen, OR 6 , CN, NR 7 R 8 CH2OR 6 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic ring, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, CO2R 6 SO3R 6 , and SO2NR 7 R 8 Selected from; A is an optionally substituted aryl or optionally substituted heteroaryl group; Each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, 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, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and amino group protecting derivatives; Each of these, in whole, is defined and described in WO 2012 / 068546 and US 2014 / 0155379, which are incorporated herein by reference.

[0197] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-jjj-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Q represents Ar or Het; E is -(CH2) m CO-, -(CH2) m SO2, -(CH2) q -,-(CH2) m NHCO-, or represents a single bond; R 1 H, OH, NH-C1~C6-alkyl, OC1~C6-alkyl, C1~C6-alkyl, C2~C6-alkenyl, C2~C6-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 ,-(CH2) q Het 1 , -CONH-(CH2) q Het 1 , -CONH-Het 1 ,-(CH2) q O-Het 1 ,-(CH2) q O-Ar 1 ,-(CH2) q Ar 1, -CONH-(CH2) q Ar 1 、-CONH-Ar 1 -CONHC3~C6-cycloalkyl, -(CH2) q Hal, -(CH2) q Cyc, CF3, -(CH2) s NH-(CH2) q -Het 1 ,-(CH2) s NH-(CH2) q -Ar 1 This represents a group where NH-C1~C6-alkyl, OC1~C6-alkyl, C1~C6-alkyl, C2~C6-alkenyl, C2~C6-alkynyl, and C3~C6-cycloalkyl groups may be substituted with one to three groups independently selected from OC1~C3-alkyl, OH, CONH2, and NH2; R 2 represents H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Hal, CF3, preferably H; R 3 Het 1 Ar 1 , NR a R b ,COOH,-(CH2) q Het 1 ,-(CH2) q Ar 1 ,-(CH2) q NR a R b ,-(CH2) q COOH, or C1-C6-alkyl, where 1-3 hydrogen atoms can be independently replaced by OH or CF3; R 4 H represents H, C1-C6 alkyl, C2-C6 alkenyl, and Hal; R a 'H' represents a linear, branched, or cyclic C1-C6 alkyl group; R b H, Het b Ar b ,-CO-Het b ,-CO-Ar b, represents a C3-C8 cycloalkyl or a linear or branched alkyl group having 1 to 6 carbon atoms, where 1 to 3 hydrogen atoms are Het b Ar b It can be replaced by NH2, N(C1~C6-alkyl)2, NH(C1~C6-alkyl), N(C1~C6-alkyl)(C3~C8-cycloalkyl), NH(C3~C8-cycloalkyl), O(C1~C6-alkyl), CN, OH, CF3, 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, or F, preferably Cl or F; Ar has 6 to 14 carbon atoms, and is Hal, C1-C6-alkyl, -(CH2) m OC1~C6-alkyl, CN, OH, NO2, CF3, -(CH2) m COOH, -(CH2) m Represents a divalent monocyclic or fused bicyclic arylene group that can be further substituted with one to four substituents selected from COOC1-C6-alkyl groups; Het has 1 to 5 heteroatoms and / or groups -C=O, independently selected from N, O, and S, and Hal, C1-C6-alkyl, -(CH2) m OC1~C6-alkyl, CN, OH, NO2, CF3, -(CH2) m COOH, -(CH2) m Represents a divalent monocyclic or condensed bicyclic, unsaturated, saturated, or aromatic heterocyclic group that may be further substituted with one to four substituents selected from COOC1-C6-alkyl groups; Ar 1It has 6 to 14 carbon atoms and is either unsubstituted or has a group such as Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, straight or branched C1-C6-alkyl, cycloalkyl, -OH, -OC1-C6-alkyl, -COC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, -CH2O(C1-C6-alkyl) b -SO2NR a R b Alternatively, it represents a monocyclic or bicyclic aromatic carbocyclic ring that is monosubstituted, disubstituted, or trisubstituted with SO2(C1~C6 alkyl); Het 1 It has 1 to 4 heteroatoms and / or a CO group independently selected from N, O, and S, and is unsubstituted or Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, linear or branched C1-C6-alkyl, C3-C8-cycloalkyl, -OH, -OC1-C6-alkyl, -NH2, -N(C1-C6-alkyl)2, -COH, -COOH, -CONH2, -COC1-C6-alkyl, -NHCO(C3-C6-cycloalkyl), group R b -SO2NR a R b Alternatively, it represents a monocyclic or bicyclic (condensed, cross-linked, or spiro) saturated, unsaturated, or aromatic heterocyclic ring that is monosubstituted, disubstituted, or trisubstituted with SO2(C1-C6 alkyl); Het bThese are linear or branched C1-C6 alkyl groups, N(C1-C6-alkyl)2, NH(C1-)2, NH(C1-)2, having 1 to 4 heteroatoms and / or CO groups independently selected from N, O, and S, and being unsubstituted or Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, -OH, -OC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, or where 1 to 3 hydrogen atoms can be replaced by NH2. Represents a monocyclic or bicyclic (condensed or spiro) saturated, unsaturated, or aromatic heterocyclic ring that is monosubstituted, disubstituted, or trisubstituted by a 4- to 8-membered heterocyclic ring containing a heteroatom selected from C6-alkyl, N(C1-C6-alkyl)(C3-C8-cycloalkyl), NH(C3-C8-cycloalkyl), O(C1-C6-alkyl), CN, OH, CF3, Hal, C3-C8-cycloalkyl, or O, S, and N; Ar b These are straight-chain or branched C1-C6 alkyl groups having 6 to 14 carbon atoms, which are either unsubstituted or Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, -OH, -OC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, or in which 1 to 3 hydrogen atoms can be replaced by NH2. Represents a monocyclic or bicyclic aromatic carbocyclic ring that is monosubstituted, disubstituted, or trisubstituted by a 4- to 8-membered heterocyclic ring containing heteroatoms selected from 6-alkyl)2, NH(C1~C6-alkyl), N(C1~C6-alkyl)(C3~C8-cycloalkyl), NH(C3~C8-cycloalkyl), O(C1~C6-alkyl), CN, OH, CF3, Hal, C3~C8-cycloalkyl, or O, S, and N; Cyc has 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, and 1 to 5 H atoms are group R such as Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, linear or branched C1-C6-alkyl, cycloalkyl, -OH, -OC1-C6-alkyl, -COC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, -CH2O(C1-C6-alkyl) b -SO2NR a R b Or it represents a saturated or partially unsaturated carbocyclic ring replaced by SO2(C1~C6 alkyl); or Each of these, in whole, is defined and described in WO 2012 / 084704 and US 2013 / 0274241, which are incorporated herein by reference.

[0198] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-kkk-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: R 1 is aryl, heteroaryl, heterocyclyl or (C 1~6 Alkyl)R 6 Here, these aryl, heteroaryl, and heterocyclyl groups are halo, cyano, and R. 4 , C 3~8 Cycloalkyl, C 1~3 Aminoalkyl, C 1~3 Hydroxyalkyl, OR 4 , NR 4 R 5 , NR 4 COR6 , NR 4 SO2R 6 SO2NR 4 R 5 CONR 4 R 5 and CONR 4 R 5 They are optionally substituted with one or two substituents selected from the group consisting of; R 2 are aryl, heteroaryl, and C 3~8 Cycloalkyl, heterocyclyl or (C 1~6 Alkyl)R 6 Here, the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are halo, cyano, oxo, hydroxyl, imino, hydroxyimino, and R. 4 , OR 4 , O(C 3~8 Cycloalkyl), (C=O)OR 4 , SO m R 6 , SO m R 4 , NR 4 R 5 SO2NR 4 R 5 and NR 4 SO2R 6 They are 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 , SO m R 4 NR 4 R 5 Or (C=O)NR 4 R 5 , NR 4 (CO)R 6 , SO m NR 4 R 5 and NR 4 SO2R 6 and; R 4 is hydrogen or C 1~6 It is an alkyl group, where this alkyl group is optionally substituted with 1 to 3 halos or hydroxyls; R 5 is hydrogen or C 1~6 It is an alkyl group, where this alkyl group is optionally substituted with a halo or hydroxyl group; R 6 are aryl, heteroaryl, and C 3~8 It is a cycloalkyl or heterocycline; m is an integer between 0 and 2; Each of these, in whole, is defined and described in WO 2012 / 129258 and US 2014 / 0194404, which are incorporated herein by reference.

[0199] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-lll-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is either -N= or -CH=; Y is -NR 2 A group consisting of -, -CH2-, -CHR-, and -O- is selected, and as a result, if Y is -CHR-, then R and R 3 These, together with the carbon atoms to which they are bonded, optionally form a 4- to 6-membered cycloalkyl ring, cycloalkenyl ring, or heterocyclic ring, where this 4- to 6-membered cycloalkyl ring, cycloalkenyl ring, or heterocyclic ring is C 1~4 Alkyl, C 3~6 Cycloalkyl, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR8 , -SR 8 , -OR 8 , -SO2R 8 , -COR 8 , -NHCOR 8 , and -CONHR 8 It is substituted as needed with 1 to 3 substituents independently selected from the group consisting of; or Y is -NR 2 -If R 2 and R 3 These, together with the nitrogen atoms to which they are bonded, form a 4- to 6-membered heterocyclic ring as needed, where this 4- to 6-membered heterocyclic ring is C 1~4 Alkyl, C 3~6 Cycloalkyl, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR 8 , -SR 8 , -OR 8 , -SO2R 8 , -COR 8 , -NHCOR 8 , and -CONHR 8 It is 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 , -SO2R 7 , -COR 7 , -NHCOR 7 , and -CONHR 7 Selected from the group consisting of; where this alkyl, cycloalkyl, aryl, and heterocyclyl is C 1~4 Alkyl, C 3~6 Cycloalkyl, CN, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR 8 , -SR 8 , -OR 8 , -SO2R 8 , -COR 8, -NHCOR 8 , and -CONHR S It is substituted as needed with 1 to 3 substituents independently selected from the group consisting of the following, where this -NHR 8 is -N(C 1~4 Alkyl)NH2 or -N(C 3~6 Substituted with cycloalkyl)NH2 as needed; R 2 is hydrogen, C 1~10 Alkyl, and C 3~8 Selected from the group consisting of cycloalkyl groups; R 3 is hydrogen, C 1~10 Alkyl, C 3~8 Cycloalkyl, aryl, heterocyclyl, and -COOR 7 Selected from the group consisting of; where this alkyl, cycloalkyl, aryl, and heterocyclyl is C 1~4 Alkyl, C 3~6 Cycloalkyl, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR 8 , -SR 8 , -OR 8 , -SO2R 8 , -COR 8 , -NHCOR 8 , and -CONHR 8 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of; R 6 C 1~10 Alkyl, C 3~8 Cycloalkyl, aryl, heterocyclyl, -COOR 7 , -SO2R 7 , and -COR 7 Selected from the group consisting of; where this alkyl, cycloalkyl, aryl, and heterocyclyl is C 1~4 Alkyl, C 3~6 Cycloalkyl, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR 8 , -SR 8 , -OR 8 , -SO2R8 , -COR 8 , -NHCOR 8 , and -CONHR 8 It is 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 this alkyl, cycloalkyl, aryl, and heterocyclyl is C 1~4 Alkyl, C 3~6 Cycloalkyl, phenyl, CF3, heterocyclyl, halogen, -COOR 8 , -NHR 8 , -SR 8 , -OR 8 , -SO2R 8 , -COR 8 , -NHCOR 8 , and -CONHR 8 It is 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 groups; Each of these, in whole, is defined and described in WO 2013 / 066729 and US 2014 / 0329799, which are incorporated herein by reference.

[0200] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, formula I-mmm-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is independently either CH or N; Y is either 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 a (C3-C8) cycloalkenyl, aryl, or heterocycle optionally substituted with one to three substituents independently selected from R1; R1 is H, oxo, (C=O) a O b (C1~C 10 ) alkyl, (C=O) a O b -aryl, (C=O) a O b (C2~C 10 ) Alkenyl, (C=O) a O b (C2~C 10 ) Alkinyl, CO2H, Halo, OH, O b (C1~C6) fluoroalkyl, (C=O) a NR5R6, CN, (C=O) a O b (C3~C8) Cycloalkyl, S(O) m NR5R6, SH, S(O) m -(C1~C 10 ) alkyl and (C=O) a O b - Selected from heterocyclyls, these alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyls are R a Substituted as needed with one or more substituents selected from; R2 and R3 are independently substituted as needed with one or more substituents selected from R1, H, (C=O) a O b C1~C 10 Alkyl, (C=O) a O b Aryl, C2~C 10 Alkenyl, C2~C 10 Alkinyl, (C=O) a O bHeterocyclyl, CO2H, CN, O b C1-C6 fluoroalkyl, O a (C=O) b NR5R6, CHO, (N=O)R5R6, S(O) m NR5R6, SH, S(O) m -(C1~C 10 ) alkyl, (C=O) a O b R2 and R3, together with the nitrogen to which they are bonded, may form a monocyclic or bicyclic heterocycle having 3 to 7 members in each ring, and optionally containing one or two further heteroatoms selected from N, O, and S in addition to this nitrogen, the monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents selected from R1; R4 is independently selected from (C1-C6) alkyl, OH, methoxy, CF3, and F, where the alkyl is optionally substituted with OH; R5 and R6 are independently H, (C=O) a O b (C1~C 10 ) alkyl, (C=O) a O b -aryl, (C=O) a O b (C2~C 10 ) Alkenyl, (C=O) a O b (C2~C 10 ) Alkinyl, CO2H, O b (C1~C6) fluoroalkyl, (C=O) a N(R a )2, CN, (C=O) a O b (C3~C8) Cycloalkyl, S(O) m N(R a )2, SH, S(O) m -(C1~C 10 ) alkyl and (C=O) a O b- Selected from heterocyclyls, these alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyls are R a Substituted as needed with one or more substituents selected from; R a R is independent of b OH, (C1~C6)alkoxy, halogen, cyclopropyl, CO2H, CN, O a (C=O) b (C1~C6) alkyl, oxo, and N(R) b ) Selected from 2; and R b These are independently selected from H and (C1-C6) alkyl groups; Each of these, in whole, is defined and described in WO 2014 / 058685 and US 2015 / 0299224, which are incorporated herein by reference.

[0201] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-nnn-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is either CH or N; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; Ring A is a (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, aryl, or heterocycle optionally substituted with one to three substituents independently selected from R1; R1 is H, oxo, (C=O) a O b (C1~C 10 ) alkyl, (C=O) a Ob -aryl, (C=O) a O b (C2~C 10 ) Alkenyl, (C=O) a O b (C2~C 10 ) Alkinyl, CO2H, Halo, OH, O b (C1~C6) fluoroalkyl, (C=O) a NR5R6, CN, (C=O) a O b (C3~C8) Cycloalkyl, S(O) m NR5R6, SH, S(O) m -(C1~C 10 ) alkyl and (C=O) a O b - Selected from heterocyclyls, these alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyls are R a Substituted as needed with one or more substituents selected from; R2 and R3 are independently substituted as needed with one or more substituents selected from R1, H, (C=O) a O b C1~C 10 Alkyl, (C=O) a O b Aryl, C2~C 10 Alkenyl, C2~C 10 Alkinyl, (C=O) a O b Heterocyclyl, CO2H, CN, O b C1-C6 fluoroalkyl, O a (C=O) b NR5R6, CHO, (N=O)R5R6, S(O) m NR5R6, SH, S(O) m -(C1~C 10 ) alkyl, (C=O) a O bR2 and R3, together with the nitrogen to which they are bonded, may form a monocyclic or bicyclic heterocycle having 3 to 7 members in each ring, and optionally containing one or two further heteroatoms selected from N, O, and S in addition to this nitrogen, the monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents selected from R1; R4 is R a Selected from (C1-C6) alkyl and (C3-C6) cycloalkyl groups as needed; R5 and R6 are independently H, oxo, (C=O) a O b (C1~C 10 ) alkyl, (C=O) a O b -aryl, (C=O) a O b (C2~C 10 ) Alkenyl, (C=O) a O b (C2~C 10 ) Alkinyl, CO2H, O b (C1~C6) fluoroalkyl, (C=O) a N(R a )2, CN, (C=O) a O b (C3~C8) Cycloalkyl, S(O) m N(R a )2, SH, S(O) m -(C1~C 10 ) alkyl and (C=O) a O b - Selected from heterocyclyls, these alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyls are R a Substituted as needed with one or more substituents selected from; R a R is independent of b OH, (C1~C6)alkoxy, halogen, cyclopropyl, CO2H, CN, O a (C=O) b(C1~C6) alkyl, oxo, and N(R) b ) Selected from 2; and R b These are independently selected from H and (C1-C6) alkyl groups; Each of these terms, in whole, is defined and described in WO 2014 / 058691 and US 2015 / 0274708, which are incorporated herein by reference.

[0202] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-nnn'-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and each of the variable products R3, R4, X, and ring A is as defined and described in WO 2014 / 058691, each of which is incorporated herein by reference.

[0203] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-ooo-1 [ka] We provide compounds of formula I, I', or II that form a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Z is the base [ka] This represents; here X is either CH or N; Y is either CH or N; Ra, Rc, and R1 each independently represent H, Hal, or A1; Rb is either H or an alkyl group; Al is a molecular chain or linear alkyl having 1 to 12 C atoms, where 1 or more, for example 1 to 7 H atoms may be replaced by Hal, ORb, COORb, CN or N(Rb)2, and 1 or more, preferably 1 to 5 CH2 groups may be replaced by O, CO, NRb or S, SO, SO2, 1,2-, 1,3- or 1,4-phenylene, -CH=CH- or -C≡C-; and Hal represents F, Cl, Br, and I; Each of these terms, in whole, is defined and described in WO 2014 / 121931 and US 2015 / 0376167, which are incorporated herein by reference.

[0204] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-ppp-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Each of R1 and R3 is independent of the other, H, (CH2) p CON(R5)2, OA, Hal, COOH, COOA, (CH2) p NHCOA, (CH2) p Het1, (CH2) p NR2R5, or OH; R2 represents a linear or branched alkyl group having H or one, two, or three C atoms, where one or two H atoms of this alkyl group are replaced as necessary by OR6, NR5R6, NHCOR5, CONR5R6; R4 represents H or A; R5 represents a linear or branched alkyl group having H or one, two, or three C atoms; R6 represents a linear or branched alkyl group having H or one, two, or three C atoms; Z is either nonexistent or represents Ar-Zyl or Het-Zyl; L is (CH2) n This represents a configuration where one or two CH2 groups are replaced as necessary by O and / or CH=CH- groups, and / or one or two H atoms are replaced as necessary by OR2, NR2R5, or Het1; Ar-diyl represents 1,2-, 1,3-, or 1,4-phenylene, optionally substituted with 1 to 5 groups independently selected from the group consisting of Hal, CN, -CF3, -OCF3, OH, OA, SO2-A, COOH, COOA, -CO-A, O-phenyl, SO2-phenyl, SO2-CF3, Het2, and A; Het-diyl represents an unsaturated, saturated, or aromatic five- or six-membered heterocycle containing one or two N, O, and / or S atoms, which may be unsubstituted or monosubstituted, disubstituted, or trisubstituted with Hal, CN, -CF3, -OCF3, OA, SO2-A, COOH, COOA, -CO-A, O-phenyl, SO2-phenyl, SO2-CF3, Het2, and / or A; A represents an unbranched or branched alkyl group containing 1 to 10 carbon atoms, where 1 to 5 hydrogen atoms are replaced by fluorine as necessary, and / or where 1 or 2 non-adjacent CH2 groups are replaced by oxygen as necessary; Het1 represents morpholinil, piperidinil, or pyrrolidinil; Het2 represents morpholinil, piperidinil, or pyrrolidinil; Hal represents F, Cl, Br, and I; n represents 1, 2, 3, 4, 5, or 6; p represents 0, 1, or 2; Each of these, in whole, is defined and described in WO 2014 / 121942 and US 2015 / 0376206, which are incorporated herein by reference.

[0205] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-qqq-1 [ka] We provide a compound of formula I, forming a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is between 0 and 4; Each R 1 These are independently -R, halogen, -CN, -NO2, -OR, -CH2OR, -SR, -N(R)2, -SO2R, -SO2N(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 -NRSO2R; or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen or optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, aryl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; R z These are -R, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -OR, or -SO 2 N(R)² is; 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 in this chain are independently replaced as needed by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO2-; Each of these terms, in whole, is defined and described in WO 2012 / 097013 and US 2012 / 0283238, which are incorporated herein by reference.

[0206] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-rrr-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is between 0 and 4; Each R 1 Independently, -R, halogen, -CN, -NO2, -OR, -CH2OR, -SR, -N(R)2, -SO2R, -SO2N(R)2, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -C(O)N(R)-OR, -NRC(O)OR, -NRC(O)N(R)2, Cy, or -NRSO2R; or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Ring B is a cyclopent or cyclohexo-condensed ring; m is 1 to 2; p is between 0 and 2; W is N; R z These are R, CN, NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)C(O)OR, -NRC(O)N(R)2, -OR, or -SO2N(R)2; L 1 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO2-; Each L 2 They are independent, covalent, or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO2-; Each R 4These are independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -SO2R, -SO2N(R)2, -SOR, -C(O)R, -CO2R, -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)2N(R)2, -NRSO2R, or a group optionally substituted, where this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: 2 -L 2 (R 4 ) p -R 4 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of these, in whole, is defined and described in WO 2013 / 106535 and US 2013 / 0231328, which are incorporated herein by reference.

[0207] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-sss-1 [ka] We provide a compound of formula I, forming a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is between 0 and 4; Each R 1 Independently, -R, halogen, -CN, -NO2, -OR, -CH2OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -SOR, -C(O)R, -CO2R, -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)2R, or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; 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; where ring B may be optionally substituted with one or more oxo, thioxo, or imino groups; m is between 0 and 4; p is between 0 and 2; W is N or -C(R 3 )-and; R z These are R, CN, NO2, 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)2N(R)2; R 3 Hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 It is a haloaliphatic, -OR, -C(O)R, or -C(O)N(R)2; L 1 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; Each L 2 They are independent, covalent, or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; and Each R 4 These are independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -CO2R, -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)2N(R)2, -N(R)S(O)2R, or optionally substituted groups, where these optionally substituted groups are C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 2 -L 2 (R 4 ) p -R 4 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed or bridged bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of these, in whole, is defined and described in WO 2014 / 011902 and US 2014 / 0018343, which are incorporated herein by reference.

[0208] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-ttt-1 [ka] We provide a compound of formula I, forming a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is between 0 and 4; Each R 1 Independently, -R, halogen, -CN, -NO2, -OR, -CH2OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)-OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; 2 R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Ring B is selected from 4- to 8-membered partially unsaturated carbocyclic fused rings, as well as 4- to 7-membered partially unsaturated heterocyclic fused rings having one or two heteroatoms selected from nitrogen, oxygen, and sulfur; where ring B may be substituted as needed with one or more oxo, thiono, or imino groups; m is between 0 and 4; p is between 0 and 2; R z These are -R, -CN, -NO2, 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)2N(R)2; R 3 Hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 It is a haloaliphatic, -OR, -C(O)R, or -C(O)N(R)2; L 1 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; Each L 2 They are independent, covalent, or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; and Each R 4These are independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(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)2N(R)2, -N(R)S(O)2R, or optionally substituted groups, where these optionally substituted groups are C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 2 -L 2 (R 4 ) p -R 4 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spiro-condensed, or bridged bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; As defined and described in WO 2014 / 011906 and US 2014 / 0018357, each of these in whole is incorporated herein by reference.

[0209] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-uuu-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is between 0 and 4; Each R 1 Independently, -R, halogen, -CN, -NO2, -OR, -CH2OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)-OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; R x and R y Each of these is independently -R, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(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)2R, or: R x and R y Together with the atoms between them, m entities exist [ka] Forms a ring B substituted with; Ring B is selected from a benzo-fused ring, a 4- to 8-membered partially unsaturated carbocyclic fused ring, a 4- to 8-membered partially unsaturated heterocyclic fused ring having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaromatic fused ring having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; where ring B may be optionally substituted with one or more oxo, thiono, or imino groups; m is between 0 and 4; p is between 0 and 2; Q is either -O- or -N(R)-, W is N or -C(R 3 )-and; R z These are -R, -CN, -NO2, 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)2N(R)2; R 3 Hydrogen, halogen, -CN, C 1~4 aliphatic, C 1~4 It is a haloaliphatic, -OR, -C(O)R, or -C(O)N(R)2; L 1 is a covalent bond or C 1~6A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; Each L 2 They are independent, covalent, or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; and Each R 4 These are independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(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)2N(R)2, -N(R)S(O)2R, or optionally substituted groups, where these optionally substituted groups are C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 2 -L 2 (R 4 ) p -R 4 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spiro, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of these terms, in whole, is defined and described in WO 2014 / 011911 and US 2014 / 0018361, which are incorporated herein by reference.

[0210] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, equation I-vvv-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Q is CH, C-CN, or N; X is CL 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 saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1 and R 1’ Each of these is independent of -R 2 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C 1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Each R 2 C 1~6 A optionally substituted group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having one or four heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 These are independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(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)2N(R)2, -N(R)S(O)2R, or optionally substituted groups, where these optionally substituted groups are C 1~6Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2; R z is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2; [Ar] is the R of m examples 1’ A phenyl or heteroaromatic ring substituted by; L 1 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; L 2 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; m is between 0 and 4; n is 0 to 4; and p is between 0 and 2; Each of these, in whole, is defined and described in WO 2015 / 048281 and US 2015 / 0094305, which are incorporated herein by reference.

[0211] In some embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] And so, equation I-vvv'-1: [ka] We provide a compound of formula I that forms a compound of or a pharmaceutically acceptable salt thereof, and here L and LBM are as defined above and as described in the embodiments herein; A, B, C, D, E, F, G, H, X 1 , X 2 , and X 3 Each of them is independently a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; and R 1 , R 2 , R 3 , and R 4 Each of these is independently a hydrogen atom or a substituted group, and this substituted group is C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: R 1 and R 2 , and R 3 and R 4 Each of these atoms, as needed, joins with the atoms between them to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0212] Such IRAK4 inhibitors are well known to those skilled in the art and include those 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 present invention relates to IRAK as 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] We provide a compound of formula I that forms a compound of or a pharmaceutically acceptable salt thereof, and here L and LBM are as defined above and as described in the embodiments herein; X 1 , X 2 , and X 3 Each of them is independently a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; and R 1 , R 2 , R 3 , and R 4 Each of these is independently a hydrogen atom or a substituted group, and this substituted group is C 1~6 Selected from 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: R 1 and R 2 , or R 3 and R 4 These atoms, together as needed with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0214] In certain embodiments, the present invention relates to an inhibitor of IRAK1 and / or IRAK4. [ka] Therefore, formula I-www-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: Q is either =N- or =CH-; Ring A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 1 -R is independent. 2 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)C(O)NR2, Cy, or -N(R)S(O)2R; or R 1 The formula is as follows: [ka] One of the following will be selected; Or two R 1 The groups, together with the atoms between them, form optionally substituted 4- to 7-membered condensed, spirocondensed, or bridging bicyclic rings having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, or a 4- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted; Each R is independently a hydrogen atom or a optionally substituted group, and this optionally substituted group is C1~6 Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic formula having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen atom, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen; Each R 2 C 1~6 A optionally substituted group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having one or four heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 and R 6 Each of them independently contains hydrogen or -L 2 (R 4 ) p -R x is; or R 5 and R 6 These atoms, together with the atoms between them, form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 These are independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -N(R)C(O)R, -N(R)C(O)NR2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O)2NR2, -N(R)S(O)2R, or a group optionally substituted, where this optionally substituted group is C 1~6Selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)NR2, -C(O)OR, -C(O)R, -NR2, -NH[Ar], -OR, or -S(O)2NR2; R z is hydrogen, -R 2 -CN, -NO2, halogen, -C(O)NR2, -C(O)OR, -C(O)R, -NR2, -NH[Ar], -OR, or -S(O)2NR2; [Ar] is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from optionally substituted phenyl, or nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; L 2 is a covalent bond or C 1~6 A divalent hydrocarbon chain, where one or two methylene units in this chain are independently replaced as needed by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; m is between 0 and 4; n is 0 to 4; and p is between 0 and 2; Each of these, in whole, is defined and described in WO 2015 / 164374 and US 2015 / 0329498, which are incorporated herein by reference.

[0215] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, formula I-xxx-1 [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X and X' each independently, CR 8 , N or -N + -O - And Y is independent of N, -N + -O - or CR 8’ And; however, at least one of X, X', or Y is N or -N. + -O - And not either, and one or less of X, X', or Y is -N + -O - and; R 1 C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; -(CR 3a R 3b ) m -(3-membered to 7-membered cycloalkyl); having 1 to 3 heteroatoms -(CR 3a R 3b ) m -(3-membered to 7-membered heterocycloalkyl); having 1 to 3 heteroatoms -(CR 3a R 3b ) m -(5-membered to 10-membered heteroaryl); or -(CR 3a R 3b ) m -C6~C 12It is an aryl; where this alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is one to five halogens, deuterium, -OR 5 , -SR 5 , -NR 11a R 11b , substituted as needed with cyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; R 2 is, -(CR 3a R 3b ) m -(3-membered to 10-membered cycloalkyl); having 1 to 3 heteroatoms -(CR 3a R 3b ) m -(3-membered to 10-membered heterocycloalkyl); having 1 to 3 heteroatoms -(CR 3a R 3b ) m -(5-membered to 10-membered heteroaryl); or -(CR 3a R 3b ) m -C6~C 12 It is an aryl; here this cycloalkyl, heterocycloalkyl, heteroaryl, or aryl has 1 to 5 R 4 It is substituted as needed; and if the heteroatom of this heterocycloalkyl and heteroaryl is N, then this N is R 4’ It is replaced as needed; or R 2 The alkyl group is C1-C6 alkyl, where this alkyl group is optionally substituted with NH2, OH, or cyano; R 3a and R 3b For each entity, it is independently either hydrogen or a C1-C3 alkyl group; R 4 For each entity, independently, the following are defined: bond, deutherium halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, oxo, -OR 5 , -SR 5 ,-S(O)R 9 -S(O)2R 9 , -NR 11a R11b , -C(O)R 10 ,-(CR 3a R 3b ) n -(3-membered to 7-membered cycloalkyl), -(CR 3a R 3b ) n -(4-membered to 10-membered heterocycloalkyl) having 1 to 3 heteroatoms, -(CR 3a R 3b ) n -(5-membered to 10-membered heteroaryl) having 1 to 3 heteroatoms, or -(CR 3a R 3b ) n -C6~C 12 It is an aryl, where this alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl each independently contains 1 to 5 deuterium, halogen, OR 5 , -SR 5 , -NR 11a R 11b , substituted as needed with cyano, C1-C6 alkyl, C3-C6 cycloalkyl or -C1-C6 alkoxy; or two R 4 These atoms, together with the carbon atoms to which they are bonded, form 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl groups, where these cycloalkyl or heterocycloalkyl groups contain 1 to 3 halogens, deuterium, or -OR 5 , -SR 5 , -NR 11a R 11b , optionally substituted with cyano or C1-C6 alkyl or C1-C6 alkoxy, where this alkyl or alkoxy is halogen, deuterium, -OR 5 , -SR 5 , -NR 11a R 11b , or substituted with cyano as needed; and if the heteroatom of this heterocycloalkyl is N, then this N is R 4’ It is replaced as needed; R 4’These are independently C1-C6 alkyl, C2-C6 alkenyl, and -C(O)R 10 -S(O)2R 9 ,-(CR 3a R 3b ) n -(3-membered to 7-membered cycloalkyl), -(CR 3a R 3b ) n -(4-membered to 10-membered heterocycloalkyl) or C(O)(CH2) t CN; where this alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is independently substituted as needed with 1 to 5 deutherium, halogen, OH, cyano, or C1-C6 alkoxy; or R 4 and R 4’ These, together with the respective atoms to which they are bonded, form 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl groups, where this cycloalkyl or heterocycloalkyl group contains 1 to 3 halogens, deuterium, -OR 5 , -SR 5 , -NR 11a R 11b , optionally substituted with cyano, C1-C6 alkyl or C1-C6 alkoxy, where this alkyl or alkoxy is halogen, deutherium, -OR 5 , -SR 5 , -NR 11a R 11b , or substituted with cyano as needed; R 5 These are independently hydrogen or C1-C6 alkyl, where this alkyl is a halogen, deutherium, C1-C6 alkoxy, C1-C6 alkylthiolyl, -NR 11a R 11b , substituted as needed with cyano, C1-C6 alkyl or C3-C6 cycloalkyl; or two R 5 These, together with the oxygen atom to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group; R 6 is -C(O)NHR 7 CO2R7 or cyano; R 7 is hydrogen or a C1-C6 alkyl group; Each R 8 These are independently hydrogen, halogen, cyano, -OR 5 , -SR 5 , -NR 11a R 11b , C6 alkyl, C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl or aryl, where this alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl contains 1 to 3 halogens, -NR 11a R 11b , OR 5 , -SR 5 , cyano, C1~C3 alkyl, -C(O)R 10 Alternatively, it may be substituted with oxo as needed; R 8’ is hydrogen, deutherium, halogen, cyano, -OR 5 , -SR 5 or NR 11a R 11b and; R 9 is, -(CR 3a R 3b ) p -(C1~C3 alkyl), -(CR 3a R 3b ) p -(4-membered to 6-membered cycloalkyl), -(CR 3a R 3b ) p -(4-membered to 6-membered heterocycloalkyl) or -(CR 3a R 3b ) p -(C5-C9 aryl), where this alkyl, cycloalkyl, heterocycloalkyl, or aryl is substituted with a fluoro or C1-C3 alkyl as needed; R 10 The alkyl group is a C1-C6 alkyl group, where this alkyl group is optionally substituted with deutherium, halogen, OH, C1-C6 alkoxy, or cyano; R11a and R 11b Each of these is independently hydrogen or a C1-C6 alkyl group, where the alkyl group is optionally substituted with deutherium, C1-C6 alkoxy, or cyano; and if it is a C2-C6 alkyl group, this alkyl group is optionally substituted with deutherium, C1-C6 alkoxy, cyano, halogen, or OH; m is independently 0, 1, 2, or 3; n is independently 0, 1, 2, or 3; p is independently either 0 or 1; and t is 1, 2, or 3; Each of these, in whole, is defined and described in WO 2015 / 150995 and US 2015 / 0284405, which are incorporated herein by reference.

[0216] In certain embodiments, the present invention relates to IRAK as an IRAK4 inhibitor. [ka] Therefore, equation I-yyy-1 or I-yyy-2: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and LBM are as defined above and described in the embodiments herein, and: X is either N or CH. m is either 1 or 2; Ar is an aryl or heteroaryl that is substituted as needed; 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 1~6Alkyl-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 It is an alkoxy; and R 2 is hydrogen or C 1~6 It is alkyl; Each of these, in whole, is defined and described in WO 2012 / 007375 and US 2012 / 0015962, which are incorporated herein by reference.

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

[0218] In some embodiments, IRAK is an IRAK binding portion that can bind to IRAK-1. In some embodiments, IRAK is an IRAK binding portion that can bind to IRAK-2. In some embodiments, IRAK is an IRAK binding portion that can bind to IRAK-3. In some embodiments, IRAK is an IRAK binding portion that can bind to IRAK-4.

[0219] In some embodiments, IRAK is selected from the portions 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, for example, AU-5850, AU-2807, AU-6686, and AU-5792, where [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0220] In some embodiments, IRAK is a portion of the compound described in Scott, J. Set 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. Chem. Manuscript, Nov. 29 2017, 10.1021 / acs.jmedchem.7b01290, for example: [ka] [ka] [ka] [ka] Selected from, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0221] In some embodiments, IRAK is a portion described in Powers, JP 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0222] In some embodiments, IRAK is a part of the structure described in 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0223] In some embodiments, IRAK is a portion described in 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0224] In some embodiments, IRAK is a portion of the information described in 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0225] In some embodiments, IRAK is a portion of the IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma, Clin. Can. Res., 2017, 23(7):1748-59, for example: [ka] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0226] In some embodiments, IRAK is the portion described in 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

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

[0228] In some embodiments, IRAK is the portion 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, for example: BMS-986126 Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0229] In some embodiments, IRAK is a portion of the part 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0230] In some embodiments, IRAK is a portion of the information described in Kelly, PNet 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0231] In some embodiments, IRAK is a part of 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0232] In some embodiments, IRAK is the portion 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0233] In some embodiments, IRAK is a part of Chiang, EY 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0234] In some embodiments, IRAK is a portion of the compound described in Lee, K. Let 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 (IRAK4), by Fragment-Based Drug Design, J. Med. Chem., 2017, 60(13):5521-42, for example: [ka] [ka] [ka] [ka] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0235] In some embodiments, IRAK is a portion of the description in 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0236] In some embodiments, IRAK is selected from the portions described in Song, K.Wet 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, for example: RO0884, RO1679, or RO6245, where [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0237] In some embodiments, IRAK is selected from the portions described in 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, for example: IRAK-IN-1A, JNK-IN-7, and JNK-IN-8, where [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0238] In some embodiments, the IRAK ligand is a portion of the portion described in McElroy, WT, 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0239] In some embodiments, the IRAK ligand is a portion described in Seganish, WM, 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0240] In some embodiments, the IRAK ligand is a portion of the information described in Seganish, WM, 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0241] In some embodiments, the IRAK ligand is the portion described in McElroy, WT, 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0242] In some embodiments, the IRAK ligand is a portion of the information described in Tumey, LN, 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] Selected from the above, here [ka] It is bonded to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0243] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-zzz: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and X, Y, R1, R2, and R3 are as defined and described in WO 2018 / 209012, which is incorporated herein by reference in whole.

[0244] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-aaaa: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and R1, R2, R3, R4, R5, R6, and R7 are as defined and described in US 2018 / 0230157, which is incorporated herein by reference in whole.

[0245] In certain embodiments, the present invention relates to the IRAK1 and / or IRAK4 coupling portion. [ka] and; As a result, equation I-bbbb: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and ring A1, ring B, ring C, L 1A , R 1 , R 2 , R 3 , R 4n, and p are defined and described as in WO 2018 / 098367, which is incorporated herein by reference in whole.

[0246] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-cccc: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 This is defined and described in WO 2018 / 052058, which is incorporated herein by reference in its entirety.

[0247] In certain embodiments, the present invention relates to the IRAK1 and / or IRAK4 coupling portion. [ka] and; Therefore, equation I-dddd: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and ring A, ring B, R 1 , R 2 , and R 3 This is defined and described in its entirety in US 2017 / 0369476, which is incorporated herein by reference.

[0248] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; This results in equation I-eeee: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and R 1 , R 2 , R 3 , and R 4 This is defined and described in WO 2017 / 207385, which is incorporated herein by reference in its entirety.

[0249] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-ffff: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and rings A, X, Y, L 1 Cy 1 Cy 2 , R 1 , R 8 , R 9 k, m, and n are defined and described in WO 2017 / 205766, which is incorporated herein by reference in whole.

[0250] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-gggg: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and ring A, L 1 Cy 1 Cy 2 , R 1 R 8 , R 9 m, and n are defined and described in WO 2017 / 205762, which is incorporated herein by reference in whole.

[0251] In a particular embodiment, the present invention relates to the IRAK4 coupling portion. [ka] and; Therefore, equation I-hhhh: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and IRAK are as defined above and described in the embodiments herein, and rings A, R 1 , R 3 , R 4 , R 5 , and R 16 This is defined and described in WO 2017 / 108723, which is incorporated herein by reference in its entirety.

[0252] In certain embodiments, the present invention relates to the IRAK1 and / or IRAK4 coupling portion. [ka] and; thereby providing a compound of formula I which forms a compound of formula I-iiii:

Chem.

[0253] In certain embodiments, the invention provides a compound of formula I wherein IRAK is an IRAK4 binding moiety

Chem.

Chem.

[0254] In certain embodiments, the invention provides a compound of formula I wherein IRAK is an IRAK4 binding moiety

Chem.

[0255] In a particular embodiment, the present invention is such that IRAK is the IRAK-4 binding portion, thereby formula I-III: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and DIM are as defined above and described in the embodiments herein, and variable R 1 , R 2 , and R 3 Each of these is as described and defined in WO 2017 / 148902 and US 2019 / 071432, each of which is incorporated herein by reference.

[0256] In a particular embodiment, the present invention is such that IRAK is the IRAK-4 coupling portion, thereby formula I-mmmm: [ka] We provide a compound of formula I, which forms a compound of or a pharmaceutically acceptable salt thereof, where L and DIM are as defined above and described in the embodiments herein, and variable R 1, R 2 , and R 3 Each of them, and each of them as a whole, are as described and defined in WO 2017 / 108744, which is incorporated herein by reference.

[0257] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] In some embodiments, IRAK is [ka] That is the case.

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

[0259] As defined above and as described herein, L is the divalent moiety that binds IRAK to LBM.

[0260] In some embodiments, L is the divalent portion that binds IRAK to LBM.

[0261] In some embodiments, L is a covalent, or divalent, saturated or unsaturated, linear or branched C 1~50It is a hydrocarbon chain, where L has 0 to 6 methylene units that are independent of -C(D)(H)-, -C(D)2-, -CRF-, -CF2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, [ka] It has been replaced by, here: Each -Cy- is independently a phenylenyl, an 8- to 10-membered bicyclic aryrenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclilenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclilenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclilenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclilen with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 11-membered molecule with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A optionally substituted divalent ring selected from saturated or partially unsaturated spiroheterorenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryrenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryrenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 a divalent phenylenyl, optionally substituted. In some embodiments, each -Cy- is independently an 8- to 10-membered bicyclic aryrenyl, optionally substituted. In some embodiments, each -Cy- is independently a 4- to 7-membered saturated or partially unsaturated carbocyclilenyl, optionally substituted. In some embodiments, each -Cy- is independently an 4- to 11-membered saturated or partially unsaturated spirocarbocyclilenyl, optionally substituted. In some embodiments, each -Cy- is independently an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclilenyl, optionally substituted. In some embodiments, each -Cy- is independently a 4- to 7-membered saturated or partially unsaturated heterocyclilenyl, optionally having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is an optionally substituted 4- to 11-membered saturated or partially unsaturated spiroheterocyclelenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclelenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is an optionally substituted 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is an optionally substituted 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0263] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] In some embodiments, -Cy- is [ka] That is the case.

[0264] In ...

Claims

1. Formula I-a-4: 【Chemical 1220】 A compound of or a pharmaceutically acceptable salt thereof, wherein: R ｘ and R ｙ Each of these is independently selected from halogens, -CN, C1-6 aliphatic, and -OC1-6 aliphatic; x is either 0 or 1; and y is either 0 or 1; L is -(C 1-10 aliphatic)-NR-(C 1-10 aliphatic)-, -Cy-NR-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-Cy-NR-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-NR-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-Cy-NR-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR-Cy-(C 1-10 aliphatic)-,-(C 1-10 aliphatic)-O-(C 1-10 aliphatic)-, -Cy-O-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-O-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-Cy-O-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)- aliphatic)-Cy-(C1-10 aliphatic)-O-(C1-10 aliphatic)-, -Cy-(C1-10 aliphatic)-Cy-O-(C1-10 aliphatic)-, -Cy-(C1-10 aliphatic)-O-Cy-(C1-10 aliphatic)-, -Cy-(C1-10 aliphatic)- aliphatic)-,-(C 1-10 (Aliphatic)-Cy-(C1-10 aliphatic)-, -Cy-(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-, or -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-; Each -Cy- is independently a divalent ring selected from 4- to 7-membered saturated carbocyclilenyl, 4- to 7-membered saturated heterocyclilenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7- to 11-membered saturated spiroheterocyclilenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic saturated heterocyclilenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each -Cy- is optionally substituted with 1 to 2 fluoro or methyl groups; IRAK is an IRAK coupling portion, and the IRAK coupling portion is 【Chemical 1221】 or a pharmaceutically acceptable salt thereof, where, Ring A is cyclobutyl or cyclohexyl; Ring B is phenyl, 【Chemical 1222】 And; Ring C is a 5- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from phenyl or nitrogen, oxygen, and sulfur. Each of L2 and L3 is a covalent bond; R1 is hydrogen, C1-6 alkyl, fluoro, chloro, -CN, -OR, -CFR2, -CF2(R), -CF3, -CR2(OR), -C(O)OR, or -C(O)NR2; Each R2 is hydrogen, C1-6 alkyl, fluoro, chloro, -CN, -OR, -NR2, -CFR2, -CF2(R), or -CF3; Each R is independently selected from groups consisting of hydrogen, or 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from C1-6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R4 is selected from a 5- to 11-membered saturated or partially unsaturated bicyclic, bridging bicyclic, or spiroheterocyclic ring having 1 to 3 heteroatoms independently selected from hydrogen, nitrogen, oxygen, and sulfur; n is either 0 or 1; and m is 0, 1, or 2. A compound or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound is given by the following formula: 【Chemical 1223】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Ring B is 【Chemical 1224】 The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

4. The compound is of the following formula: 【Chemistry 1225】 【Chemical 1226】 One of the compounds described in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. Ring C is phenyl, 【Chemical 1227】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or -OMe.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl, fluoro, chloro, -CN, -OR, -CFR2, -CF2(R), or -CF3.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4 is a saturated or partially unsaturated 5- to 11-membered ring, a bridging bicyclic, or spiroheterocyclic ring having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. L is -(C 1-10 aliphatic)-NR-(C 1-10 aliphatic)-, -Cy-NR-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-Cy-NR-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-O-(C 1-10 aliphatic)-, -Cy-O-(C 1-10 aliphatic)-, -(C 1-10 aliphatic)-Cy-O-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-, or -(C 1-10 aliphatic) -Cy-(C 1-10 A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is aliphatic.

10. The compound is of the following formula: 【Chemical 1228】 One of the compounds described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. The aforementioned IRAK coupling portion 【Chemical 1229】 【Chemical 1230】 A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound, 【Chemical 1231】 【Chemical 1232】 【Chemical 1233】 【Chemical 1234】 【Chemical 1235】 【Chemical 1236】 【Chemical 1237】 【Chemical 1238】 【Chemical 1239】 【Chemistry 1240】 【Chemistry 1241】 【Chemistry 1242】 【Chemical 1243】 A compound according to any one of claims 1 to 11, selected from any one of the compounds shown, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

14. The pharmaceutical composition according to claim 13, further comprising an additional therapeutic agent.

15. 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 12, or a pharmaceutically acceptable salt thereof, wherein the method comprises the step of administering the compound, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient or bringing it into contact with the biological sample.

16. 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 12, or a pharmaceutically acceptable salt thereof.

17. The composition according to claim 16, characterized in that the composition is administered in combination with an additional therapeutic agent.

18. The composition according to claim 16, 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 disorders, metabolic disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

19. The composition according to claim 16, wherein the disorder, disease, or condition mediated by IRAK4 is selected from MyD88 drive disorders.

20. The composition according to claim 19, wherein the MyD88-driven dysfunction is selected from ABC DLBCL, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

21. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for treating an IRAK4-mediated disorder, disease, or condition in a patient.

22. The use according to claim 21, further comprising treating the patient with an additional therapeutic agent.

23. The use according to claim 21, 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 disorders, metabolic disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

24. The use according to claim 21, wherein the malfunction, disease, or condition mediated by IRAK4 is selected from MyD88 drive malfunctions.

25. The use according to claim 24, wherein the MyD88-driven dysfunction is selected from ABC DLBCL, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

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