IRAK degraders and uses thereof

Abstract

To provide IRAK degraders and uses thereof.SOLUTION: The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM, a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders. Compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of one or more IRAK protein kinases. In some embodiments, a provided compound degrades and / or inhibits IRAK-1 / 2 / 3 / 4.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 868,609 (filed June 28, 2019), U.S. Provisional Application No. 62 / 875,407 (filed July 17, 2019), U.S. Provisional Application No. 62 / 908,153 (filed September 30, 2019), U.S. Provisional Application No. 62 / 944,834 (filed December 6, 2019), and U.S. Provisional Application No. 62 / 948,96 No. 62 / 964,955 (filed January 23, 2020), and U.S. Provisional Application No. 63 / 040,891 (filed June 18, 2020), the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to the use of ubiquitination and / or degradation of one or more of the compounds according to the present invention. or more of the regulation of interleukin-1 receptor-associated kinase ("IRAK"). The present invention relates to compounds and methods useful for treating pharmaceutically acceptable salts of the compounds of the present invention. Possible compositions and methods of using the compositions in the treatment of various disorders are also provided. [Background technology]

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) regulates key regulatory proteins. It is an important pathway that blocks and degrades misfolded or abnormal proteins. The UPP is central to many cellular processes and when it is defective or impaired, When this mismatch occurs, it can lead to the onset of various diseases. Covalent attachment to is achieved through the action of an E3 ubiquitin ligase.

[0004] Over 600 E3 ubiquitins facilitate the ubiquitination of a wide variety of proteins in vivo. There are four families of HECT-domain E3 ligases: , U-box E3s, monomeric RING E3s, and multisubunit E3s In general, Li et al. (PLOS One, 2008, 3, 1487) titled "G enome-wide and functional annotation of human E3 ubiquitin ligases identify MU LAN, a mitochondrial E3 that regulates t he organelle's dynamics and signaling.''; Berndsen et al. (Nat. Struct. Mol. Biol. , 2014, 21, 301-307) titled "New insights into ubiquitin E3 ligase mechanism”;Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 3 99-434) Title: RING domain E3 ubiquitin ligase Spratt et al. (Biochem. 2014, 458, 421-437) Title: RBR E3 ubiquitin ligases: new structures, new insights, new questions .”; and Wang et al. (Nat. Rev. Cancer., 20 14, 14, 233-347) Title: “Roles of F-box protei ns in cancer.

[0005] The UPP mediates various fundamental cellular processes, including regulation of the cell cycle, cell surface receptors, and ion transporters. It is a short-lived regulatory protein important in the regulation of ATP channels and antigen presentation. It plays a major role in the breakdown of proteins. The pathway is involved in several forms of malignancy, several genetic disorders, and Genetic disorders (cystic fibrosis, Angelman syndrome, and Liddle syndrome) are involved in the pathogenesis of viral infections (including HIV), immune surveillance / viral pathogenesis, and the pathology of muscle wasting. Many diseases are associated with abnormal UPP, which affects the cell cycle and division, stress, and Cellular responses to stimuli and extracellular modulators, morphogenesis of neural networks, cell surface receptors, Adversely affecting the regulation of ion channels, secondary pathways, DNA repair, and organelle biogenesis It is available.

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

[0007] UPP is used to induce selective proteolysis, targeting proteins and We artificially ubiquitinated synthetic small molecule probes to induce proteasome-dependent degradation. This includes the use of fusion proteins to target protein binding ligands and E3 ubiquitins. Bifunctional compounds consisting of ubiquitin ligase ligands have been shown to bind to these E3 ubiquitin ligases. of selected proteins to the proteasome through recruitment and subsequent ubiquitination These drug-like molecules induce the temporal regulation of protein expression. Such compounds offer the possibility of being added to cells or administered to animals or humans. Upon addition, it may induce inactivation of a protein of interest and may be useful as a biochemical reagent. and new methods for treating disease by removing pathogenic or oncogenic proteins. (Crews C, Chemistry & Biology, 2 010,17(6):551-555;Schnnekloth JS Jr.,Che mbiochem,2005,6(l):40-46). The art has been devoted to the effective treatment of diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, there is a continuing need to address non-specific effects and specific classes of proteins. The inability to target and regulate multiple factors (e.g., transcription factors) together can prevent effective anti-cancer drugs. Therefore, protein catalysis mediated by E3 ligases remains an obstacle to the development of new cancer drugs. Interleukin-1 receptor-associated kinase (IRAK) and other kinases affect the degradation of Small molecule therapeutics that target cancer-related proteins hold promise as therapeutic agents. Thus, there remains a need to find compounds that are IRAK degraders useful as therapeutic agents. [Prior art documents] [Non-patent literature]

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

[0009] Summary of the Invention The present application discloses a method for recruiting IRAK kinase to an E3 ubiquitin ligase for degradation. The present invention relates to novel bifunctional compounds and methods for their preparation and use, particularly The present disclosure provides a method for the treatment of IRAK kinases (which are then treated with the bifunctional compounds described herein) Modules for targeted ubiquitination of ribosomal proteins (which are degraded and / or otherwise inhibited by The present invention provides bifunctional compounds that find utility as inhibitors of IRAK kinase targets. The ubiquitination, which is then degraded by the monovalent compounds described herein, Monovalent compounds that find utility as inducers of An advantage of the compounds provided herein is that they have a wide variety of pharmacological activities. This is possible and is compatible with the degradation / inhibition of IRAK kinase. an effective amount of a compound described herein to treat a disease state such as cancer, e.g., multiple myeloma, The present invention provides methods for use in the treatment or alleviation of In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: wherein IRAK is an IRAK binding moiety capable of binding to IRAK4, and the compound of formula I has the formula I"-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I"-a: Each R x are independently hydrogen, deuterium, R z, Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O) OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X the groups optionally taken together form an optionally substituted 5- to 6-membered partially unsaturated ring or aryl-fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spiro-fused ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, optionally taken together with atoms between them, form a 4- to 11-membered, saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring having, in addition to the atom to which they are attached, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R y are independently hydrogen, deuterium, Rz , Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R) OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] or Single R y and a single R x optionally taken together with the atoms therebetween to form an 8- to 20-membered, saturated or partially unsaturated carbocyclic or heterocyclic monocyclic or bicyclic ring having 1 to 10 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R z independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 9-membered, saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic or spirocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring P and Ring Q are optionally fused rings independently selected from phenyl or benzo, a 4- to 7-membered, saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring P and Ring Q are independently optionally substituted with 1 to 2 oxo groups; Ring T is selected from phenyl, a 4- to 7-membered, saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups; L x is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently selected from the group consisting of -Cy x and optionally replaced by -, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR- or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR- is R x or R y can combine with to form a 4- to 7-membered, saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -Cy x - is an optionally substituted ring selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy x - is optionally substituted with 1 to 2 oxo groups; X is a covalent bond or a 4- to 6-membered, saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [ka] is a single or double bond; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or unsaturated straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D)2-, -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] [ka] is replaced by Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 11-membered bicyclic arylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an 8- to 10-membered bicyclic saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; DIM is a degradation-inducing moiety, The compound or a pharmaceutically acceptable salt thereof. (Item 2) The compounds have formula Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Id-3, Id-4, Ie-1, If-1, If-2, If-3, Ig-1, Ih-1 or Ih-2: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. (Item 3) 3. The compound of claim 1 or 2, wherein the DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. (Item 4) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has the formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O) N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -O -P(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 or: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring containing, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 3. (Item 5) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has the formula I-dd: [ka] or a pharmaceutically acceptable salt thereof, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from R 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. selected from a 6-membered heteroaryl containing a heteroatom, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are independently hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] It is connected to Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6or: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring containing, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 3. (Item 6) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has the formula I-ff: [ka] or a pharmaceutically acceptable salt thereof, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from R 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are independently hydrogen, -R6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 or: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring containing, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 3. (Item 7) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has the formula I-hh: [ka] or a pharmaceutically acceptable salt thereof, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or C substituted as needed 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6or: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; The compound according to item 3. (Item 8) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has formula I-nn: [ka] or a pharmaceutically acceptable salt thereof, In formula I-nn; Ring E is [ka] is selected from X 1 , X 6 and X 7 each independently represents a covalent bond, —CH—, —CHCF—, —SO—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 3 and X 5 each is independently a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] [ka] is a trivalent moiety selected from Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 or: aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3a are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O )R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C (O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP (O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -NP(O)R2 , -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1~4 Is aliphatic; or R 7 and X 1 or X 3 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Two R on the same carbon 7 groups, optionally taken together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on adjacent carbon atoms 7groups, optionally taken together with the atoms therebetween, form a 3- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated bridged or spiroheterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; n is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; The compound according to item 3. (Item 9) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has any one of the following formulas: (i) [ka] [ka] or a pharmaceutically acceptable salt thereof, [ka] , each of X, X1, X2, Y, R1, R3, R3', R4, R5, t, m and n are as defined and described in WO2017 / 007612 and US2018 / 0134684); (ii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables A, G, G', Q1, Q2, Q3, Q4, R, R', W, X, Y, Z, [ka] and n are each as defined and described in WO2016 / 197114 and US2018 / 0147202); (iii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein variable A 1 , A 2 , A 3 , R 5 , G and Z are each as defined and described in WO2017 / 176958); (iv) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, L, x, y and [ka] TIFF2025113407000047.tif510, each as defined and described in WO2017 / 161119); (v) [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 ,X, [ka] JPEG2025113407000050.jpg68 and each of n are as defined in WO2017 / 197051, the entirety of which is incorporated herein by reference; [ka] is R 1 is bonded to R 1 and R 2 or R 12 R of the binding site of 17 is as defined in WO2017 / 197051, so that [ka] However, the R 12 occupying a substituent position); or (vi) [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and the variable R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 ,X, [ka] and n are each as defined in WO2018 / 237026, the entirety of each of which is incorporated herein by reference; and [ka] is R as defined in WO2018 / 237026 1 or R 16 To, R 12 binding site, resulting in [ka] However, the R 12 (occupying the position of a substituent) Item 3. The compound according to item 3, selected from: (Item 10) The compound has the formula Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7, Ij-1, Ij-2, Ij-3, Ij-4, Ik-1, Il-1, Il-2, Il-3, Im-1, In-1 or In-2: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. (Item 11) LBM is a VHL E3 ubiquitin ligase binding moiety, and the compound has one of the following formulas: (i) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein variable R 1’ , R 2’ , R 3’ , each of X and X' is as defined and described in WO2013 / 106643 and US2014 / 0356322); (ii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein variable R 1’ , R 2’ , R 3’ , R5, R6, R7, R9, R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X', Y, Z1, Z2, Z3, Z4 and o are as defined and described in WO2016 / 149668 and US2016 / 0272639); or (iii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein variable R p , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 and o are as defined and described in WO2016 / 118666 and US2016 / 0214972. Item 3. The compound according to item 3, selected from: (Item 12) LBM is an MDM2 E3 ubiquitin ligase binding moiety, and the compound has one of the following formulas: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R6’ , R 7’ , R 8’ , R 9’ , R 10’ , R 11’ , R 12’ , R 1” , A, A', A", X, Y, and Z are as defined and described in WO2017 / 011371 and US2017 / 0008904. Item 3. The compound according to item 3, selected from: (Item 13) LBM is an IAP E3 ubiquitin ligase binding moiety, and the compound has one of the following formulas: [ka] or a pharmaceutically acceptable salt thereof, wherein variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each as defined and described in WO2017 / 011590 and US2017 / 0037004 Item 3. The compound according to item 3, selected from: (Item 14) DIM is a lysine mimetic, and the compound has any one of the following formulas: (i) [ka] or a pharmaceutically acceptable salt thereof; and (ii) [ka] or a pharmaceutically acceptable salt thereof, wherein variable R 1 , R 4 , R 5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496. Item 3. The compound according to item 3, selected from: (Item 15) DIM is a hydrogen atom and the compound has the formula I-mmm: [ka] or a pharmaceutically acceptable salt thereof. (Item 16) L is a divalent saturated or unsaturated straight or branched chain C 1~30 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -C(D)(H)-, -C(D)2-, -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-; Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or an optionally substituted bivalent ring selected from a partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5. The compound according to any one of claims 1 to 4. (Item 17) Items 1 to 16, wherein the compound is selected from any one of the compounds depicted in Table 1 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. (Item 18) A compound according to any one of items 1 to 17, and a pharmaceutically acceptable carrier; A pharmaceutical composition containing an adjuvant or vehicle. (Item 19) 19. A method for degrading and / or inhibiting IRAK protein kinase in a patient or biological sample, comprising administering to a subject a compound according to any one of items 1 to 17 or a compound thereof. The method comprises administering to the patient or contacting with the biological sample a biological composition. (Item 20) A method for treating a disorder, disease, or condition mediated by IRAK in a patient, comprising administering to the patient a compound according to any one of items 1 to 17 or a pharmaceutical composition thereof. The method comprises administering. (Item 21) The IRAK-mediated disorder, disease or condition may be cancer, neurodegenerative disorder, viral 21. The method according to item 20, wherein the patient is selected from the group consisting of a cancer disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder. Law. (Item 22) The cancer or proliferative disorder may be a benign or malignant tumor of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, a solid tumor, a carcinoma, a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma, a gastrointestinal cancer, a colon cancer, a colorectal adenoma, a head and neck tumor, epidermal hyperplasia, psoriasis, or a prostatic hyperplasia. Diseases, neoplasms, neoplasms of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's or non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders, smoldering or indolent multiple myeloma, and leukemia, diffuse large B-cell lymphoma (DLBCL), ABC 22. The method of item 21, wherein the hematological malignancy is selected from the group consisting of DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma. (Item 23) 23. The method of item 22, wherein the MyD88-driven disorder is selected from the group consisting of ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia. (Item 24) Item 22, wherein the IL-1-driven disorder is smoldering or indolent multiple myeloma. The method described below. (Item 25) 22. The method of claim 21, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disorders caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease. (Item 26) The inflammatory disorder may be ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis; allergic rhinitis, hemolytic anemia, aplastic anemia, red blood cell anemia, idiopathic thrombocytopenia or another inflammatory disease involving an autoimmune response or having an autoimmune component or etiology, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease or another autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periodontitis, Pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, alveolar osteitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy as appropriate), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, Retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, ahidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic, non-allergic, mild, moderate, severe, bronchitis, or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD (injury, airway inflammation, bronchial hyperresponsiveness, remote Dering or reduction of disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis,Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis 22. The method according to item 21, wherein the inflammatory bowel disease is selected from the group consisting of urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0010] The present application further provides compounds of the following general formula I: [ka] or a pharmaceutically acceptable salt thereof, IRAK kinase inhibitors using bifunctional molecules, including bifunctional molecules linking the guide moieties. wherein each variable is as defined and described herein. It is.

[0011] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for targeting ubiquitination. Such compounds have now been found to be effective in modulating the activity of the steroid hormone agonist, steroid hormone agonist, and steroid hormone receptor agonist. b: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. As stated.

[0012] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful in treating diseases involving IRAK kinase. and the like. Such diseases, disorders, or conditions include those described herein. It can be obtained.

[0013] The compounds provided by the present invention also have potential for the prevention of IR in biological and pathological phenomena. Research into AK enzymes; research into intracellular signal transduction pathways occurring in body tissues; and New kinase, signaling pathway, and cytokine levels in vitro or in vivo For comparative evaluation of new IRAK inhibitors or degraders, or other regulators It is useful for DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention, and compositions thereof, may be used to inhibit one or more IRAK proteins. In some embodiments, the compounds are useful as degraders and / or inhibitors of kinases. The compounds provided degrade and / or inhibit IRAK-1 / 2 / 3 / 4.

[0015] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: IRAK is one or more of the following: IRAK-1, -2, -3, or -4 an IRAK binding moiety capable of binding to L is a bivalent moiety that binds IRAK to DIM; and DIM is a degradation-inducing moiety.

[0016] 2. Compounds and Definitions: Compounds of the invention include those generally described above, and further include compounds of the classes disclosed herein. As used herein, unless otherwise specified, Unless otherwise specified, the following definitions shall apply: For the purposes of this invention, elements Periodic Table, CAS version, Handbook of Chemistry and P Identify chemical elements according to Physics, 75th Edition. Additionally, General Principles of Organic Chemistry "Organic Chemistry," the entire contents of which are incorporated herein by reference. istry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Adva nced Organic Chemistry”, 5th ed., ed.: Smith, M.B. and March, J., John Wiley & Sons, New York:2 It was written in 001.

[0017] The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, fully saturated or containing one or is a hydrocarbon chain containing more unsaturated units, or is fully saturated or has only one or Monocyclic or bicyclic hydrocarbons containing one or more unsaturated units but which are not aromatic Hydrocarbons (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl" ) that has one point of attachment to the rest of the molecule. In some embodiments, the aliphatic group contains 1 to 6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In yet other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms. aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains 1-2 In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") is fully saturated or has one or more alkyl groups. Monocyclic C rings containing unsaturated units but which are not aromatic and have one point of attachment to the rest of the molecule Suitable aliphatic groups include straight or branched chain, saturated or unsaturated. Saturated 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" refers to a saturated or partially unsaturated, Any bicyclic ring system (i.e., carbocyclic or heterocyclic) having at least one bridge As defined by IUPAC, a "bridge" is a multi-atom bond connecting two bridgeheads. an unbranched chain, or one atom, or valence bond, of Any skeletal atom in the ring system that is bonded to the skeletal atom (other than hydrogen) above. In this embodiment, the bridged bicyclic group has 7 to 12 ring members and independently nitrogen, oxygen, or sulfur. are well known in the art, and each group may be attached to any suitable carbon or nitrogen atom. Unless otherwise specified, the groups include those described below, which are attached to the remainder of the molecule via A bridged bicyclic group may optionally be substituted with one or more substituents as described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group may be optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0019] The term "lower alkyl" refers to C 1~4 The term "alkyl" refers to a straight or branched chain alkyl group of the formula: Suitable lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term "lower haloalkyl" refers to a group substituted with one or more halogen atoms. There is, C 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

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

[0022] The term "unsaturated" as used herein refers to one or more unsaturated It means a part having a unit.

[0023] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturation or "Unsaturated, linear or branched hydrocarbon chain" means a linear or branched hydrocarbon chain, as defined herein. refers to a divalent alkylene chain, alkenylene chain, or alkynylene chain, which may be branched or unbranched. .

[0024] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a The aryl group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6. , 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain may be one or more. More methylene hydrogens are replaced with substituents, resulting in a polymethylene group. Substituents include those described below for substituted aliphatic groups.

[0025] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain may have at least one at least one double bond, and one or more hydrogen atoms are replaced by substituents Suitable substituents include those listed below for substituted aliphatic groups. The following are examples of such materials:

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

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

[0028] Alone or as "aralkyl", "aralkoxy" or "aryloxyalkyl" The term "aryl" when used as part of a larger moiety, such as in "aryl," means has a total of 5 to 14 ring members, at least one ring in the system is aromatic, and The term "acyclic" refers to a monocyclic or bicyclic ring system in which each ring in the system contains from 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In the present context, "aryl" refers to an aromatic ring system, including phenyl, biphenyl, naphthyl, and anthracyl, which may be present in one or more It may have more substituents. Also included within the scope are compounds in which an aromatic ring is fused to one or more non-aromatic rings. groups such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or or tetrahydronaphthyl).

[0029] Either alone or as a larger moiety (e.g., "heteroaralkyl" or "heteroaralkyl"). The terms "heteroaryl" and "heteroara-" are used as part of the term "heteroaryl" or "heteroaryloxy" ("alkoxy"). has 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; cyclic have 6, 10, or 14 pi electrons shared in the configuration; and in addition to the carbon atom The term "heteroatom" refers to a group having 1 to 5 heteroatoms. refers to sulfur, and any oxidized form of nitrogen or sulfur, and any quaternary form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, phenyl ... Loryl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, iso Oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl Diazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyl The terms "heteroaryl" and "heteroaradinyl" are used interchangeably. "-" also refers to a heteroaromatic ring having one or more aromatic rings. fused to a cyclic, alicyclic, or heterocyclic ring, the radical or point of attachment of which is Non-limiting examples include indolyl, isopropyl, and propyl groups on the heteroaromatic ring. Indolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzo Imidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl , phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroquinolinyl Hydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" is intended to encompass any of the terms "heteroaryl ring," "heteroaryl group," or " "heteroaromatic" and "heteroaromatic" may be used interchangeably, and any of these terms may be optionally substituted. The term "heteroaralkyl" includes rings substituted by heteroaryl. wherein the alkyl and heteroaryl moieties independently optionally are substituted accordingly.

[0030] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical" and "heterocyclic "Heterocyclic ring" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic ring. or a 7- to 10-membered bicyclic heterocyclic moiety of the formula, which may be saturated or partially unsaturated. and in addition to the carbon atoms, have one or more, preferably 1 to 4 heteroatoms as defined above. When used, the term "nitrogen" includes substituted nitrogens. Examples include oxygen, sulfur, or or nitrogen in a saturated or partially unsaturated ring In this case, the nitrogen was N (as in 3,4-dihydro-2H-pyrrolyl). whether it is NH (as in pyrrolidinyl), + NR (N-substituted pyrrolidinyl (as in

[0031] A heterocyclic ring may be attached to its parent group at any heteroatom or carbon atom that results in a stable structure. and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuran ... Tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl quinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, o Xazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazolidinyl Examples of compounds that may be used include azepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" " and "heterocyclic radical" are used interchangeably herein and also include heterocyclic radicals. The tetracyclyl ring may be one or more aryl, heteroaryl, or alicyclic rings. Groups fused to the formula ring (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthrin, Heterocyclyl groups include monocyclic rings (e.g., quinolinyl, thorizinyl, or tetrahydroquinolinyl). The term "heterocyclylalkyl" refers to a heterocyclyl and the alkyl moiety and the heterocyclyl group are substituted with aryl. The moieties are independently optionally substituted.

[0032] As used herein, the term "partially unsaturated" means a group having at least one double bond or The term "partially unsaturated" refers to a ring moiety containing multiple sites of unsaturation. is intended to include, but is not limited to, an aryl moiety or heteroaryl moiety as defined herein. It is not intended to encompass aryl moieties.

[0033] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted" refers to a group of groups, whether or not preceded by the term "optionally." Unless otherwise specified, one or more hydrogens on the specified moiety may be replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group is Suitable substituents may be present on each substitutable portion of the group, and may occur in more than one group in any given structure. When more than one position can be substituted with more than one substituent selected from a particular group, The substituents at each position may be the same or different. Combinations of substituents envisioned by this invention preferably result in stable compounds or those that are chemically The term "stable" as used herein means a combination that results in the formation of a compound that is stable. When used, their generation, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed. A compound that does not change substantially when subjected to conditions that allow its use.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently and halogen; -(CH2) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2)0 ~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ ) 2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ can be replaced by );-(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ may be substituted with );-C H=CHPh (This is R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○ -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 ○ ;-(CH2) 0~4 OC(O)NR ○ 2;-C( O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C (NOR ○ )R ○ ;-(CH2) 0~4 SSR○ ;-(CH2) 0~4 S(O)2R ○ ; -(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O )2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;- N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2 R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (5- to 6-membered heteroaryl ring ), or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having the above structure. Regardless of definition, R ○ The two independent entities of together with 0 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms independently selected from nitrogen, oxygen, or sulfur atoms. a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic ring having a heteroatom; or Forms a bicyclic ring, which may be substituted as defined below.

[0035] R ○ (R ○ It is formed by combining two independent entities of the atom between them. Suitable monovalent substituents on the ring (including the ring) are independently halogen, -(CH2), 0~2 R ● ,-(halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH (OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2)0 ~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3.- C(O)SR ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● ,Ma or-SSR ● where each R ● is unsubstituted or preceded by "halo" and, if present, is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or independently nitrogen, oxygen, or a 5- or 6-membered saturated ring having 0 to 4 heteroatoms selected from sulfur, R is selected from an unsaturated ring or an aryl ring. ○ Suitable divalent substitutions on saturated carbon atoms of Groups include ═O and ═S.

[0036] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: Examples include: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O ) OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~ 3O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of hydrogen , which may be substituted as defined below 1~6 Aliphatic, or independently nitrogen, oxygen, or sulfur. , a partially unsaturated ring, or an aryl ring. Suitable divalent substituents attached to vicinal substitutable carbons include -O(CR * 2) 2~ 3O-, where R * Each independent occurrence of is hydrogen, substituted as defined below C can be 1~6 aliphatic or 0 independently selected from nitrogen, oxygen, or sulfur Unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings containing up to four heteroatoms The ring is selected from the group consisting of aryl rings.

[0037] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -O H, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2, -NHR ● , -NR ● 2, or -NO2, where each R ● is replaced If there is no halogen atom, or if preceded by "halo", it may be replaced by one or more halogen atoms only. are exchanged, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur is a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having the following structure:

[0038] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O) CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † teeth independently hydrogen, C which may be substituted as defined below 1~6 Aliphatic, unsubstituted-OPh or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring; or Notwithstanding the above definition, R † The two independent entities of together with 0 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms independently selected from nitrogen, oxygen, or sulfur atoms. Unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic rings containing aryl atoms Forms a ring or bicyclic ring.

[0039] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● ,- NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is replaced If there is no halogen atom, or if preceded by "halo", it may be replaced by one or more halogen atoms only. are exchanged, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur is a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having the following structure:

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

[0041] As used herein, the term "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable based on sound medical judgment. within the limits of the range of 100mg / kg, without excessive toxicity, irritation, allergic response, etc., to humans and lower animals. suitable for use in contact with tissue and commensurate with a reasonable benefit / risk ratio , salts. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., J. Pharmaceutical Sci ences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include suitable inorganic salts. These include salts derived from inorganic acids, inorganic bases, organic acids, and organic bases. Examples of possible non-toxic acid addition salts are those formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like. 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 ion exchange or other methods known in the art. Other drugs are salts of amino groups formed by other methods used in Clinically acceptable salts include adipate, alginate, ascorbate, and aspartate. Salt, benzenesulfonate, benzoate, bisulfate, borate, butyrate, sulphate Salt, camphorsulfonate, citrate, cyclopentanepropionate, diglyceride Luconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate Phosphate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, Hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, la Phosphate, lauryl sulfate, malate, maleate, malonate, methanesulfonate Acid salts, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates , palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, Phosphate, pivalate, propionate, stearate, succinate, sulfate, tartaric acid salts, such as thiocyanate, p-toluenesulfonate, undecanoate, and valerate Examples include:

[0042] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and the like. nium salts and N + (C 1~4 Typical examples of alkali metal salts include or alkaline earth metal salts, such as sodium, lithium, potassium, calcium, and Further pharmaceutically acceptable salts, where appropriate, include: Halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions Counterions such as ions, lower alkyl sulfonate ions, and aryl sulfonate ions Non-toxic ammonium, quaternary ammonium, and amine cations formed using Includes

[0043] Unless otherwise stated, structures depicted herein also represent all isomeric forms of that structure. (e.g., enantiomers, diastereomers, and geometric (or conformational) forms, e.g., For example, R and S configurations for each asymmetric center, Z and E double bond isomers, and It is intended to encompass both Z and E conformational isomers. Chemical isomers, as well as enantiomers, diastereomers, and geometric (or conformational) isomers Mixtures are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are The isomeric forms are within the scope of the present invention. The resulting structures also differ only in the presence of one or more isotopically enriched atoms. This means that compounds containing hydrogen can be included. For example, hydrogen can be included in compounds containing deuterium or tritium. The structure of the present invention in which carbon is replaced by 13 C or 14 C is enriched carbon Compounds having the substituted invention are within the scope of the present invention. For example, as analytical tools according to the present invention, as probes in biological assays, These compounds are useful as therapeutic agents.

[0044] As used herein, the term "inhibitor" refers to an inhibitor that inhibits IRAK kinase with measurable affinity. In certain embodiments, the term "antibody" is defined as a compound that binds to and / or inhibits the activity of an antibody. and the inhibitor is less than about 50M, less than about 1M, less than about 500nM, less than about 100nM, IC of less than about 10 nM, or less than about 1 nM 50 and / or have a binding constant.

[0045] As used herein, the term "degrader" refers to a degrader that binds an IRAK kinase and an E3 ligase. and / or inhibit both with measurable affinity to ubiquitinate the IRAK kinase. Defined as heterobifunctional or monovalent compounds that lead to chitinization and subsequent degradation In certain embodiments, the degrading agent is less than about 50M, less than about 1M, less than about 500 DC of less than nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM 50 This book As used herein, the term "monovalent" refers to a molecule that does not have an E3 ligase binding moiety attached. Decomposer compounds.

[0046] The compounds of the present invention may be tethered to a detectable moiety. Such compounds may be used as imaging agents. It will be understood that the detectable moiety is useful in various applications. It is recognized that the compound may be attached to a suitable compound. "Detectable substituent" refers to a moiety that can be covalently attached to a detectable moiety. Such moieties are well known in the art. These are well known to those skilled in the art and include, for example, carbonate moieties, amino moieties, thiol moieties, to name a few. Examples of such moieties include groups containing an ol or hydroxyl moiety. The compound may be directly attached to the target compound or may be attached via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. It is understood that such moieties may be attached as follows: In some embodiments, such The moiety can be obtained by 1,3-cycloaddition of azides with alkynes, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art. , Rostovtsev et al.,Angew.Chem.Int.Ed.2002,41,2 596-99 and Sun et al., Bioconjugate Chem., 2006, 17 ,52-57.

[0047] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to a moiety that is capable of being detected. Any moiety that can be labeled, such as a primary label and a secondary label, includes radioisotopes (e.g., For example, tritium, 32 P, 33 P,35 S, or 14 C), mass tags, and fluorescent labels Primary labels, such as , are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0048] As used herein, the term "secondary label" refers to a label that is attached to a secondary intermediate for the production of a detectable signal. Biotin and various protein antigens are moieties that require the presence of an interbody. For antigens, a streptavidin-enzyme conjugate may be included as a secondary intermediate. For labeling, secondary intermediates may include antibody-enzyme conjugates. These transfer energy in a non-radiative process of fluorescence resonance energy transfer (FRET). It acts as a secondary label as it is transferred to another group and the second group produces a signal that is detected.

[0049] As used herein, the terms "fluorescent label," "fluorochrome," and "fluorophore" refer to a specific excitation A moiety that absorbs light energy at an excitation wavelength and emits light energy at a different wavelength. Examples of labels include Alexa Fluor dyes (Alexa Fluor 350, Ale xa Fluor488, Alexa Fluor532, Alexa Fluor54 6, Alexa Fluor568, Alexa Fluor594, Alexa Fl uor633, Alexa Fluor660 and Alexa Fluor680), AMCA, AMCA-S, BODIPY dye (BODIPY FL, BODIPY R6 G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BOD IPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, B ODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665 ), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), cascade block Lu, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3. 5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumaric acid Fluorescein, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF , eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDye s(IRD40, IRD700, IRD800), JOE, Lissamine Rhodamine B, Mali Nablue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Gon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyre Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetra Tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Examples of red pigments include, but are not limited to, Kissus Red and Texas Red-X.

[0050] As used herein, the term "mass tag" refers to a molecule that can be detected using mass spectrometry (MS) detection techniques. Mass tags are any moiety that can be uniquely detected by its mass. Examples of mass tags include N-[3- [4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methyl Lyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(penta Fluorophenoxyl)methylacetophenone and its derivatives The synthesis and utility of these mass tags are described in U.S. Patent No. 4,629,666, and U.S. Patent No. 4,629,666. No. 650,750, No. 4,709,016, No. 5,360,8191, No. 5,516 , No. 931, No. 5,602,273, No. 5,604,104, No. 5,610,020 and 5,650,270. Other examples of mass tags include various Nucleotides, dideoxynucleotides, oligonucleotides, Oligopeptides, oligosaccharides and other synthetic polymers of various lengths and monomer compositions Suitable mass range (100 to 2000 daltons) A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, The mass tag may be a smeared or unsmeared object.

[0051] The terms "measurable affinity" and "measurably inhibit" are used herein to refer to In this case, the compound of the present invention or a composition thereof and an IRAK protein kinase The sample and the sample containing the IRAK protein kinase in the absence of the compound or composition thereof. This means that there is a measurable change in IRAK protein kinase activity between equivalent samples. do.

[0052] 3. Description of Exemplary Embodiments: As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, IRAK is one or more of the following: IRAK-1, -2, -3, or -4 an IRAK binding moiety capable of binding to L is a bivalent moiety that binds IRAK to DIM; and DIM is a degradation-inducing moiety.

[0053] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, IRAK is the IRAK-4 binding moiety; L is a bivalent moiety that binds IRAK to DIM; and DIM is an LBM, a lysine mimetic, or a hydrogen atom. IRAK binding part (IRAK)

[0054] In certain embodiments, the present invention relates to a method for treating IRAK-4-associated leukemia, wherein the IRAK is an IRAK-4 binding moiety, Thus, formula Ia or Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM and L are as defined above and as described in embodiments herein. the law of nature, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(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)R 2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same carbon or nitrogen atom may be combined with the atoms between them as needed. In addition to carbon or nitrogen, 0 to 3 independently selected from nitrogen, oxygen and sulfur forming a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring containing a heteroatom of ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring P and ring Q are each a phenyl or benzo, 4- to 7-membered, saturated or partially unsaturated carbon atom. a heterocyclic ring or 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 1 to 4 rings independently selected from nitrogen, oxygen, and sulfur; Optionally, independently selected from 5- to 6-membered heteroaryl rings having a heteroatom. wherein ring P and ring Q are independently 1 to 2 oxo groups, if necessary. are substituted accordingly; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 6-membered heteroaryl rings, wherein Ring T is further selected from 1 to 2 oxo groups. have been substituted as necessary; L x is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogen fluoride chain, wherein one to two methylene units of said chain are independently -Cy x -,- O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - Replaced as needed by NR-, -N=CR-, -CR=CR- or -S(O)2- where -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR -R is R x or R y In combination with 4- to 7-membered saturated or partially unsaturated carbon a heterocyclic ring or a ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; can form a heterocyclic ring having -Cy x - represents 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having Five-membered heteroatoms having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from the group consisting of -Cy and -Cy(aryl), x -teeth, optionally substituted with 1 to 2 oxo groups; X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or nitrogen atom. Heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and; [ka] is a single or double bond; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0055] In certain embodiments, the present invention relates to a method for treating IRAK-4-associated leukemia, wherein the IRAK is an IRAK-4 binding moiety, Thus, formula I'-a or I'-b: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein DIM and L are as defined above and as described in embodiments herein. the law of nature, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from independently selected from a saturated ring or an aryl-fused ring, or nitrogen, oxygen, or sulfur 3- to 5-membered saturated or partially unsaturated carbocyclic rings containing 0 to 3 heteroatoms or forming a heterocyclic spiro-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same atom, together with the atoms between them as needed, form a four-membered ~11-membered saturated or partially unsaturated carbocyclic ring or rings containing, in addition to the attached atoms, nitrogen Heterocyclic monocyclic rings having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a cyclic, bicyclic, bridged bicyclic, spiro or heteroaryl ring; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5 ,or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring P and ring Q are each a phenyl or benzo, 4- to 7-membered, saturated or partially unsaturated carbon atom. a heterocyclic ring or 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 1 to 4 rings independently selected from nitrogen, oxygen, and sulfur; Optionally, independently selected from 5- to 6-membered heteroaryl rings having a heteroatom. wherein ring P and ring Q are independently 1 to 2 oxo groups, if necessary. are substituted accordingly; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; L x is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogen fluoride chain, wherein one to two methylene units of said chain are independently -Cy x -,- O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - Replaced as needed by NR-, -N=CR-, -CR=CR- or -S(O)2- where -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR -R is R x or R y In combination with 4- to 7-membered saturated or partially unsaturated carbon a heterocyclic ring or a ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; can form a heterocyclic ring having -Cy x - represents 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having Five-membered heteroatoms having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from -Cy x -teeth, optionally substituted with 1 to 2 oxo groups; X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or nitrogen atom. Heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and; [ka] is a single or double bond; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0056] In certain embodiments, the present invention relates to a method for treating IRAK-4-associated leukemia, wherein the IRAK is an IRAK-4 binding moiety, Thus, formula I''-a or I''-b: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM and L are as defined above and as described in embodiments herein. the law of nature, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from independently selected from a saturated ring or an aryl-fused ring, or nitrogen, oxygen, or sulfur 3- to 5-membered saturated or partially unsaturated carbocyclic rings containing 0 to 3 heteroatoms or forming a heterocyclic spiro-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same atom, together with the atoms between them as needed, form a four-membered ~11-membered saturated or partially unsaturated carbocyclic ring or rings containing, in addition to the attached atoms, nitrogen Heterocyclic monocyclic rings having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a cyclic, bicyclic, bridged bicyclic, spiro or heteroaryl ring; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5 ,or [ka] or Single R y and a single R x together with the atoms between them as needed, 8- to 20-membered saturated or partially unsaturated carbocyclic or cyclic rings independently of nitrogen, oxygen, and sulfur a heterocyclic monocyclic or bicyclic ring having 1 to 10 heteroatoms selected from the following: Form; Each R z independently, C 1~6 Aliphatic, phenyl, 4- to 9-membered, saturated or partially unsaturated Carbocyclic or containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur Heterocyclic monocyclic, bicyclic, bridged bicyclic or spirocyclic rings, as well as nitrogen, acid 5- to 6-membered heteroatoms having 1 to 4 heteroatoms independently selected from nitrogen and sulfur an optionally substituted group selected from the group consisting of aryl rings; Ring P and ring Q are each a phenyl or benzo, 4- to 7-membered, saturated or partially unsaturated carbon atom. a heterocyclic ring or 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 1 to 4 rings independently selected from nitrogen, oxygen, and sulfur; Optionally, independently selected from 5- to 6-membered heteroaryl rings having a heteroatom. wherein ring P and ring Q are independently 1 to 2 oxo groups, if necessary. are substituted accordingly; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; L x is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogen fluoride chain, wherein one to two methylene units of said chain are independently -Cy x -,- O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - Replaced as needed by NR-, -N=CR-, -CR=CR- or -S(O)2- where -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR -R is R x or R y In combination with 4- to 7-membered saturated or partially unsaturated carbon a heterocyclic ring or a ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; can form a heterocyclic ring having -Cy x - represents 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having Five-membered heteroatoms having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from -Cy x -teeth, optionally substituted with 1 to 2 oxo groups; X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or nitrogen atom. Heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and; [ka] is a single or double bond; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0057] As described herein, [ka] The core structure illustrated as [ka] Includes.

[0058] As generally defined above, each R x are independently hydrogen, deuterium, R z , Ha Rogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2 NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR 2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R) OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2,- OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O) (NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or two R X The groups, optionally together, may be nitrogen, oxygen or sulfur. Optionally substituted 5-membered aryl groups having 0 to 3 heteroatoms independently selected from ~6-membered partially unsaturated ring or aryl-fused ring, or independently of nitrogen, oxygen, or sulfur 3- to 5-membered saturated or partially unsaturated heteroatoms having 0 to 3 heteroatoms selected from the group consisting of It forms a carbocyclic or heterocyclic spiro-fused ring.

[0059] In some embodiments, each R x are independently hydrogen. Hey, R x is deuterium. In some embodiments, each R x is independent Te, R z In some embodiments, each R x are independently halogen. In some embodiments, each R x are independently -CN. In some embodiments, And each R x is independently -NO. In some embodiments, each R x is independent and -OR. In some embodiments, each R x are independently -SR. In some embodiments, each R x is independently -NR2. In each R x is independently —S(O)R. In some embodiments, each R x is independently —S(O)NR. In some embodiments, each R x is German In some embodiments, each R xare independently, -CF R2. In some embodiments, each R x are independently -CF2R. In some embodiments, each R x are independently -CF. In some embodiments, And each R x is independently -CR(OR). In some embodiments, each R x is independently -CR(NR). In some embodiments, each R x is independent and -C(O)R. In some embodiments, each R x are independently -C(O ) OR. In some embodiments, each R x are independently -C(O)NR2 In some embodiments, each R x are independent, -N + (O - )R2. In some embodiments, each R x are independently -OP(O)R2. In the form, each R x are independently -OP(O)(OR). In each R x are independently -OP(O)(OR)NR. In each R x are independently -OP(O)(NR). In some embodiments, In each R x is independently -P(O)R. In some embodiments, each R x is independently -SiR. In some embodiments, each R x are independently - Si(OR)R. In some embodiments, each R x are independently -SF5 In some embodiments, each Rx is independent, [ka] In some embodiments, two R X The groups are joined together as needed to form nitrogen Optionally, having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Forms an optionally substituted 5- to 6-membered partially unsaturated ring or aryl-fused ring. In an embodiment, two R X The groups, optionally together, may be nitrogen, oxygen or sulfur. Optionally substituted 3-membered aryl groups having 0 to 3 heteroatoms independently selected from Forms a 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spiro-fused ring.

[0060] In some embodiments, R x teeth, [ka] In some embodiments, R x is fluoro. Hey, R x is -CFH. In some embodiments, R x -OMe In some embodiments, R x is -SMe. In some embodiments, R x is -Me. In some embodiments, R x is -OCF2H In some embodiments, R x is -OCF3. In some embodiments, R x is —S(O)Me. In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x is -OEt. In some embodiments, Hey, R x In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] is.

[0061] In some embodiments, each R x is selected from those illustrated in Table 1 below .

[0062] As generally defined above, each R is independently hydrogen or an optionally substituted is a group, which optionally substituted group is C 1~6 Aliphatic, phenyl, nitrogen, oxygen, and sulfur; or partially unsaturated heterocyclic, and one independently selected from nitrogen, oxygen, and sulfur a 5- to 6-membered heteroaryl ring having up to 4 heteroatoms; or Two R groups on the same atom, together with the atoms between them as needed, In addition to the atom to which it is bonded, 0 to 3 atoms independently selected from nitrogen, oxygen, and sulfur 4- to 11-membered saturated or partially unsaturated carbocyclic or heterocyclic rings containing heteroatoms It forms a monocyclic, bicyclic, bridged bicyclic, spiro, or heteroaryl ring.

[0063] In some embodiments, each R is independently hydrogen. Each R is C 1~6 is an optionally substituted group selected from aliphatic groups. In some embodiments, each R is optionally substituted phenyl. In embodiments, each R is 1 to 2 independently selected from nitrogen, oxygen, and sulfur. Optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing heteroatoms In some embodiments, each R is independently selected from nitrogen, oxygen, and sulfur. Optionally substituted 5- or 6-membered heteroaromatic rings having 1 to 4 heteroatoms selected from the group consisting of In some embodiments, two R groups on the same atom are spaced apart from each other. and, if necessary, the atoms to which they are bonded, plus nitrogen, oxygen, 4- to 11-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen and sulfur. saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro, or form a heteroaryl ring.

[0064] In some embodiments, each R is selected from those depicted in Table 1 below.

[0065] As generally defined above, each R y are independently hydrogen, deuterium, R z , Ha Rogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2 NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR 2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R) OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2,- OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O) (NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, -SF5, or [ka] or two R y The groups, optionally taken together, may be nitrogen, oxygen or sulfur. an optionally substituted 5-membered alkyl group having 0 to 3 heteroatoms independently selected from to form a 6-membered partially unsaturated ring or aryl-fused ring; or a single R y and simply First R x These, together with the atoms between them as needed, form 8- to 20-membered saturated or or partially unsaturated carbocyclic ring or 1 to 1 independently selected from nitrogen, oxygen and sulfur Forms a heterocyclic monocyclic or bicyclic ring having 0 heteroatoms.

[0066] In some embodiments, each R y are independently hydrogen. Hey, R y is deuterium. In some embodiments, each R y is independent Te, R z In some embodiments, each R y are independently halogen. In some embodiments, each R y are independently -CN. In some embodiments, And each R y is independently -NO. In some embodiments, each R y is independent and -OR. In some embodiments, each R y are independently -SR. In some embodiments, each R y is independently -NR2. In each R y is independently —S(O)R. In some embodiments, each R y is independently —S(O)NR. In some embodiments, each R y is German In some embodiments, each R y are independently, -CF R2. In some embodiments, each R y are independently -CF2R. In some embodiments, each R x are independently -CF. In some embodiments, And each R y is independently -CR(OR). In some embodiments, each R y is independently -CR(NR). In some embodiments, each R y is independent and -C(O)R. In some embodiments, each R y are independently -C(O ) OR. In some embodiments, each R y are independently -C(O)NR2 In some embodiments, each R y are independent, -N + (O - )R2. In some embodiments, each R y are independently -OP(O)R2. In the form, each R y are independently -OP(O)(OR). In each R y are independently -OP(O)(OR)NR. In each R y are independently -OP(O)(NR). In some embodiments, In each R y is independently -P(O)R. In some embodiments, each R y is independently -SiR. In some embodiments, each R y Independently, - Si(OR)R. In some embodiments, each R y are independently -SF5 In some embodiments, each R yis independent, [ka] In some embodiments, two R y The groups are joined together as needed to form nitrogen Optionally, having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Forms an optionally substituted 5- to 6-membered partially unsaturated ring or aryl-fused ring. In embodiments, a single R y and a single R x The atoms between these and, if necessary, Together they form an 8- to 20-membered saturated or partially unsaturated carbocyclic or Heterocyclic monocyclic rings or heterocyclic rings having 1 to 10 heteroatoms independently selected from aryl, arylsulfur, and sulfur. or bicyclic rings.

[0067] In some embodiments, R y is fluoro. , R y is chloro. In some embodiments, R y is -CN. In some embodiments, R y In some embodiments, R y is -CFMe2. In some embodiments, R y is -Me. In some embodiments, R y is -OCF3. In some embodiments, R y is fluoro. In some embodiments, R y is cyclopropyl. In some embodiments, R y teeth, [ka] In some embodiments, R y teeth, [ka] is.

[0068] In some embodiments, R y and R x Let's get together and [ka] In some embodiments, R y and R x Let's get together and [ka] In some embodiments, R y and R x Let's get together and [ka] In some embodiments, R y and R x Let's get together and [ka] In some embodiments, R y and R x Let's get together and [ka] is.

[0069] In some embodiments, each R y is selected from those illustrated in Table 1 below .

[0070] As generally defined above, each R z independently, C 1~6 Aliphatic, phenyl, 4-membered ~9-membered saturated or partially unsaturated carbocyclic or independently selected from nitrogen, oxygen, and sulfur a heterocyclic monocyclic, bicyclic, or bridged bicyclic ring having 1 to 2 heteroatoms, A spirocyclic ring and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Optionally substituted 5- to 6-membered heteroaryl rings having heteroatoms. It is a base.

[0071] In some embodiments, each R z independently, C 1~6 aliphatic, is an optionally substituted group. In some embodiments, each R z is independent and necessary In some embodiments, each R z is independent, It must have 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. optionally substituted 4- to 9-membered saturated or partially unsaturated carbocyclic or heterocyclic, monocyclic; In some embodiments, each R z are independently 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted 5- to 6-membered heteroaryl rings having the formula:

[0072] In some embodiments, each R z is selected from those illustrated in Table 1 below .

[0073] As generally defined above, rings P and Q are phenyl or benzo, 4- to 7-membered rings. a saturated or partially unsaturated carbocyclic ring or rings independently of nitrogen, oxygen and sulfur; Heterocyclic rings containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from and optionally fused rings independently selected from ring P and ring Q, and optionally substituted with 1 to 2 oxo groups.

[0074] In some embodiments, ring P and ring Q are independently phenyl or benzo. In some embodiments, ring P and ring Q are independently 4- to 7-membered, saturated or is a partially unsaturated carbocyclic ring or 1 to 3 independently selected from nitrogen, oxygen and sulfur In some embodiments, ring P and ring Q independently represents 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the rings P and and ring Q are independently optionally substituted with 1 to 2 oxo groups.

[0075] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] In some embodiments, ring P and ring Q are [ka] is.

[0076] In some embodiments, ring P and ring Q are selected from those depicted in Table 1 below. It is selected.

[0077] As generally defined above, ring T may be phenyl, 4- to 7-membered, saturated or partially an unsaturated carbocyclic ring or 1 to 3 rings independently selected from nitrogen, oxygen, and sulfur; a heterocyclic ring having a heteroatom or 1 independently selected from nitrogen, oxygen, and sulfur; From 5- to 9-membered monocyclic or bicyclic heteroaryl rings containing 1 to 4 heteroatoms wherein Ring T is further optionally substituted with 1 to 2 oxo groups.

[0078] In some embodiments, Ring T is from phenyl. In this embodiment, ring T is a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or a nitrogen, acid A heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen and sulfur. In some embodiments, ring T is independently selected from nitrogen, oxygen, and sulfur. 5- to 9-membered monocyclic or bicyclic heteroaryl rings containing 1 to 4 heteroatoms In some embodiments, Ring T may further optionally be substituted with 1 to 2 oxo groups. has been replaced.

[0079] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is phenyl. In this case, the ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] In some embodiments, ring T is [ka] is.

[0080] In some embodiments, ring T is selected from those depicted in Table 1 below.

[0081] As generally defined above, L x is a covalent bond, or C 1~3 If the divalent linear chain It is a branched saturated or unsaturated hydrocarbon chain, where one or two methyl groups in the chain The units are independent, -Cy x -, -O-, -S-, -C(O)-, -C(S)-, -CR 2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR- or -S( O)2-, where -CR2-, -CRF-, -NR- , -N=CR- or -CR=CR-, R is R x or R y Combined with, 4 members ~ a 7-membered saturated or partially unsaturated carbocyclic ring or rings independently selected from nitrogen, oxygen and sulfur; A heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of 1 to 3 heteroatoms can be formed.

[0082] In some embodiments, L x is a covalent bond. , L x is C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of Here, one or two methylene units in this chain are independently -Cy x -, -O-, -S-, -C (O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR -, -CR=CR- or -S(O)2- as appropriate. In the embodiment, -CR2-, -CRF-, -NR-, -N=CR- or -CR= The R in CR- stands for R x or R y In combination with 4- to 7-membered, saturated or partially unsaturated a carbocyclic ring or one to three heteroatoms independently selected from nitrogen, oxygen and sulfur It is possible to form a heterocyclic ring having the ring structure.

[0001] In some embodiments, ring L x is -C(O)N(H)-. In the embodiment, the ring L x is —CHC(O)N(H)—. In some embodiments, Leave it, L x is R y Combined with [ka] In some embodiments, L x is R y Combined with [ka] Form.

[0002] In some embodiments, ring L x is selected from those illustrated in Table 1 below .

[0003] As generally defined above, -Cy x - is independently selected from nitrogen, oxygen and sulfur A 3- to 5-membered saturated or partially unsaturated carbocyclic ring containing 0 to 3 selected heteroatoms a cyclic or heterocyclic ring, or 1 to 4 independently selected from nitrogen, oxygen and sulfur; and optionally substituted 5-membered heteroaryl rings having 1 or more heteroatoms. where -Cy x - is optionally substituted with 1 to 2 oxo groups .

[0004] In some embodiments, -Cy x - is independently selected from nitrogen, oxygen and sulfur 3- to 5-membered saturated or partially unsaturated carbocyclic ring with 0 to 3 heteroatoms The ring is an optionally substituted ring selected from a ring, a cyclic ring, or a heterocyclic ring. In the form -Cy x - is 1 to 4 independently selected from nitrogen, oxygen, and sulfur In some embodiments, the heteroaryl ring is a 5-membered heteroaryl ring having a heteroatom of -Cy x - is optionally substituted with 1 to 2 oxo groups.

[0005] In some embodiments, the ring -Cy x - is selected from those illustrated in Table 1 below will be done.

[0006] As above, X is a covalent bond or a 4- to 6-membered, saturated or partially unsaturated carbon A cyclic ring or one to two heteroatoms independently selected from nitrogen, oxygen, and sulfur It is a heterocyclic ring having

[0007] In some embodiments, X is a covalent bond. X is a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or a group consisting of nitrogen, oxygen, and sulfur. and a heterocyclic ring having 1 to 2 heteroatoms independently selected from the group consisting of:

[0008] In some embodiments, X is [ka] In some embodiments, X is [ka] is.

[0009] In some embodiments, X is selected from those depicted in Table 1 below.

[0010] As generally defined above, [ka] is a single or double bond.

[0011] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0012] In some embodiments, the ring [ka] is selected from those illustrated in Table 1 below.

[0013] As generally defined above, each of x and y is independently 0, 1, 2, 3 or It is 4.

[0014] In some embodiments, each of x and y is independently 0. In some embodiments, each of x and y is independently 1. , x and y are each independently 2. In some embodiments, each independently is 3. In some embodiments, each of x and y is independently , 4.

[0015] In some embodiments, each of x and y is selected from those depicted in Table 1 below. be selected.

[0016] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x as shown in formula I -c-1: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0017] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject ax is a thioamide as shown Formula Ic-2: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0018] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x As shown, 1,2,4-triazo and a compound of formula Ic-3: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0019] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x As shown, 1,3,4-oxazolidinyl Azoles of formula Ic-4: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0020] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x As shown, it is an oxazole , formula Ic-5: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0021] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x is a thiazole as shown in Formula Ic-6: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R x, R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0022] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a x As shown, it is imidazole , formula Ic-7: [ka] or a pharmaceutically acceptable salt thereof, wherein DIM, L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0023] In some embodiments, the present invention provides a compound in which ring P and ring Q are benzoxazoles as shown. Forming a sazole ring to form a compound of formula Id-1: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0024] In some embodiments, the present invention provides a benzothiazide ring in which rings P and Q are benzothiazide rings as shown. Forming a zole ring to give formula Id-2: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0025] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment, comprising administering to a patient a cancer treatment, a method for treating a cancer cell comprising administering to a patient a cancer treatment, and a method for treating a cancer cell ... to form a cyclohexyl ring to give formula Id-3: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0026] In some embodiments, the present invention provides a compound in which ring P and ring Q are pyrazolopyridins as shown. Forming a lysine ring to give formula Id-4: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0027] In some embodiments, the present invention provides a 5-azaizyme complex in which ring P and ring Q are as shown. to form an indazole ring to give formula Id-5: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0028] In some embodiments, the present invention provides a compound in which ring P and ring Q are imidazo[ 1,2-a]pyridine ring to form a compound of formula Id-6: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0029] In some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: R x As shown [ka] and formula Ie-1: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R y , the ring T, and y, alone and in combination, In both cases, the term "substitution" refers to a combination of two or more of the following:

[0030] In some embodiments, the present invention provides a method for treating a medicament comprising administering to a patient a method for treating a medicament, the method ... x -OR and X is cyclohexyl as shown, and has formula Ie-2: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , R x , R y , ring P, ring T, x, and y each independently represent and Both in combination as defined above and as described in embodiments herein. It is.

[0031] In some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: Single R x is -OR, and X is cyclohexyl as shown, and e-3: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , R x , R y , each of the rings T, x, and y, alone and in combination, both in combination as defined above and as described in the embodiments herein. do.

[0032] In some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: Ring T is cyclohexyl as shown, and has formula If-1: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , x, and y, alone and in combination, and wherein both are as defined above and as described in the embodiments herein. .

[0033] In some embodiments, the present invention provides rings P and Q each independently selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, ,7-tetrahydro-2H-indazole ring to form a compound of formula If-2: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0034] In some embodiments, the present invention provides a compound in which ring P and ring Q are isoindo groups as shown. Forming a phosphorus-1-one ring to give the compound of formula If-3: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0035] In some embodiments, the present invention provides a quinoline ring in which ring P and ring Q are as shown. to form a compound of formula Ig-1: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0036] In some embodiments, the present invention provides a compound in which ring P and ring Q are 2H-thienoic acid groups as shown. to form a 2,3-c]pyrazole ring, to give a compound of formula Ig-2: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0037] In some embodiments, the present invention provides a compound in which ring P is pyridine and ring Q is and phenyl of formula Ih-1: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0038] In some embodiments, the present invention provides a compound in which ring P is pyrazole and ring Q is shown. and phenyl of formula Ih-2: [ka] or a pharmaceutically acceptable salt thereof, wherein So, DIM, L, L x , X, R x , R y , each of the rings T, x, and y can be singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0039] In certain embodiments, the present invention relates to a method for treating IRAK-4-associated leukemia, wherein the IRAK is an IRAK-4 binding moiety, Thus, formula Ii: [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in embodiments herein. Variable R 1 , R 2 and R 3 Each of the above is disclosed in WO2017 / 148902 and US20 19 / 071432, each of which in its entirety is as set forth and defined in the present application. It is incorporated by reference in the specification.

[0040] In certain embodiments, the present invention relates to a method for treating IRAK-4-associated leukemia, wherein the IRAK is an IRAK-4 binding moiety, Thus, the formula Ij: [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in embodiments herein. Variable R 1 , R 2 and R 3 Each of the above is described and defined in WO2017 / 108744. and the entirety of each of which is incorporated herein by reference.

[0041] In some embodiments, IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] In some embodiments, the IRAK is [ka] is.

[0042] In some embodiments, the IRAK is selected from those depicted in Table 1 below. do. Ligase binding moiety (LBM)

[0043] As defined herein and described below, formulas are illustrated using square brackets. For example, [ka] , L is DIM or LBM, including substitution or replacement of defined groups in DIM or LBM. or attached to a modifiable carbon, oxygen, or nitrogen atom in the LBM.

[0044] In some embodiments, the DIM is LBM. The invention relates to a method for treating cereblon-associated ubiquitin ligase (LBM), which binds to the E3 ubiquitin ligase (cereblon). , Formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is selected from -CR2-, -NR-, -O-, -S- or -Si(R2)- is a bivalent moiety; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P (O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or C substituted as needed 1~4 It is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C( O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O) 2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR) (NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a 6-membered aryl, nitrogen, oxygen, or sulfur independently selected from 1 to 4. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carbo 1 to 3 independently selected from cyclyl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl having a heteroatom of a 5-membered heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from heteroaryl; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0045] -(R 2 ) m When the point of attachment of is shown on ring B, -(R 2 ) m The attachment point of is on ring A. and any available carbon atom on ring A, including the ring to which ring B is fused. It is contemplated, and will be understood by those skilled in the art, that the -R may be at the carbon atom or at the nitrogen atom. 2 but, R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist , -R 2 But this R 4 group or R 5 Occupies the -R group position. 2 But R 3 Carbon bonded to When bonded to an atom, R 3 does not exist, and -R 2 But this R 3 Occupies the base position.

[0046] In some embodiments, the compound of formula I-aa has formula I-aa′ or formula I- aa”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, ring A, L , L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above .

[0047] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the compound of formula I-bb: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is selected from -CR2-, -NR-, -O-, -S- or -Si(R2)- is a bivalent moiety; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P (O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or C substituted as needed 1~4 It is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C( O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O) 2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR) (NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] wherein ring B is an imidazo or benzo , [ka] Ring B is other than benzo, [ka] Other than that, Ring B is benzo, [ka] Other than that, Ring B is benzo, [ka] [ka] Other than that, Ring B is a 6-membered aryl, nitrogen, oxygen, or sulfur independently selected from 1 to 4. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carbo 1 to 3 independently selected from cyclyl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl having a heteroatom of a 5-membered heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from tetraaryl; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0048] -(R 2 ) m When the point of attachment of is shown on ring B, -(R 2 ) m The attachment point of is on ring A. and any available carbon atom on ring A, including the ring to which ring B is fused. It is contemplated, and will be understood by those skilled in the art, that the -R may be at the carbon atom or at the nitrogen atom. 2 but, R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist , -R 2 But this R 4 group or R 5 Occupies the -R group position. 2 But R 3 Carbon bonded to When bonded to an atom, R 3 does not exist, and -R 2 But this R 3 Occupies the base position.

[0049] In some embodiments, the compound of formula I-bb is of formula I-bb' or I- bb”: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, ring A, L , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0050] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the compound of formula I-cc: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -NR, or optionally substituted C 1~4 It is aliphatic; Each R 2 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, and is -N(R)S(O)R; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; a fused ring selected from aryl; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, and is -N(R)S(O)R; R 5 is hydrogen, C 1~4aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing 1 to 2 heteroatoms, and 5-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur a 6-membered heteroaryl ring, or Two R groups on the same nitrogen, together with the atoms between them as needed, form a and 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; It forms a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0051] -(R 2 ) m When the point of attachment of is shown on ring B, -(R 2 ) m The attachment point of is on ring A. and any available carbon atom on ring A, including the ring to which ring B is fused. It is contemplated, and will be understood by those skilled in the art, that the -R may be at the carbon atom or at the nitrogen atom. 2 but, R 4 or R 5 If bonded to a nitrogen atom bonded to R4 or R 5 does not exist , -R 2 But this R 4 group or R 5 Occupies the -R group position. 2 But R 3 Carbon bonded to When bonded to an atom, R 3 does not exist, and -R 2 But this R 3 Occupies the base position.

[0052] In some embodiments, the compound of formula I-cc above can be represented by formula I-cc' or formula I- cc”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring A, L, R 1 , R 2 , X 1 and m are each as defined above .

[0053] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the compound of formula I-dd: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is selected from -CR2-, -NR-, -O-, -S- or -Si(R2)- is a bivalent moiety; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O )(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and is replaced as necessary by C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from R 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN , -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S( O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R) C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2- , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, - N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R) P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S( O)2R; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; Selected from: Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; L 1is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] It is connected to Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0054] In some embodiments, the compound of formula I-dd is of formula I-dd' or I- dd”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m and Each of p and p is as defined above.

[0055] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the compound has the formula I-ee: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -NR, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from R 2and R 3a each independently represents hydrogen, -R 6 , halogen, -CN, -NO2, -O R, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O )R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C( -O)NR2, or -N(R)S(O)2R; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; Selected from: Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] It is connected to Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0056] In some embodiments, the compound of formula I-ee has formula I-ee' or formula I- ee”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1, n, m and p are As defined.

[0057] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the compound of formula I-ff: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is selected from -CR2-, -NR-, -O-, -S- or -Si(R2)- is a bivalent moiety; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O )(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and is replaced as necessary by C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from R 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN , -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S( O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R) C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2- , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, - N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R) P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S( O)2R; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; Selected from: Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O) OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0058] In some embodiments, the compound of formula I-ff can be represented by formula I-ff' or formula I- ff”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n and Each of p and p is as defined above.

[0059] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the moiety has the formula I-gg: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -NR, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from R 2 , R 3a and R 4 each independently represents hydrogen, -R 6 , halogen, -CN, -NO2 , -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O )R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(O)NR2, or -N(R)S(O)2R; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; Selected from: R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0 or 1, Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them as needed, form the In addition to nitrogen, the compound has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The rings form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0060] In some embodiments, the compound of formula I-gg has formula I-gg′ or formula I- gg”: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1 , m, n and p are each As defined.

[0061] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the moiety has the formula I-hh: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is selected from a covalent bond, -CR2-, -NR-, -O-, -S- or -SiR2- is a bivalent moiety that is R 1 is absent or is hydrogen, deuterium, halogen, -CN, -OR, -SR, - S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2) OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3 , or C substituted as needed 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O) R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C (R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O) R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O )(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R) C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O )(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring E, ring F and ring G each independently comprise a 6-membered aryl, nitrogen, oxygen or sulfur. 6-membered heteroaryl containing 1 to 4 independently selected heteroatoms; 5-membered to 7-membered heteroaryl saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur 5- to 7-membered saturated or partially unsaturated alkyl group having 1 to 3 heteroatoms independently selected from the group consisting of saturated heterocyclyl, or 1 to 4 independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from a 5-membered heteroaryl having 1 or 2 heteroatoms, wherein the ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups. ; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , or 16.

[0062] [ka] is shown on ring E, ring F or ring G, [ka] The point of attachment of is on ring E, ring F, or ring G, including the ring to which ring E or ring G is fused to ring F. It is intended that the atom may be any available carbon or nitrogen atom of the I understand.

[0063] -(R 2 ) m When the attachment point of -(R 2 ) m The point of attachment of ring E, ring F or ring G is at the carbon atom where ring E or ring G is fused to ring F. It is intended that ring G may be any available carbon or nitrogen atom, and The business owner understands.

[0064] [ka] is shown on ring E, ring F or ring G, [ka] The point of attachment of ring E, ring F or ring G is at the carbon atom where ring E or ring G is fused to ring F. It is intended that ring G may be any available carbon or nitrogen atom, and The business owner understands.

[0065] In some embodiments, the compound of formula I-hh has formula I-hh' or formula I- hh”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring E, Ring F, Ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m, respectively. is as defined above.

[0066] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the moiety has the formula I-hh-1 or I-hh-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O) R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C (R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O) R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O )(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R) C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O )(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring E, ring F and ring G each independently comprise a 6-membered aryl, nitrogen, oxygen or sulfur. 6-membered heteroaryl containing 1 to 4 independently selected heteroatoms; 5-membered to 7-membered heteroaryl saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur 5- to 7-membered saturated or partially unsaturated alkyl group having 1 to 3 heteroatoms independently selected from the group consisting of saturated heterocyclyl, or 1 to 4 independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from a 5-membered heteroaryl having 1 or 2 heteroatoms, wherein the ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups. ; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~61 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , or 16, R 4 , R 10 , R 11 , R 15 , W 1 , W 2 , and X is a member of WO 2019 / 09986 8, each of which is incorporated herein by reference in its entirety. .

[0067] [ka] is shown on ring E, ring F or ring G, [ka] The point of attachment of is on ring E, ring F, or ring G, including the ring to which ring E or ring G is fused to ring F. It is intended that the atom may be any available carbon or nitrogen atom of the I understand.

[0068] -(R 2 ) m When the attachment point of -(R 2 ) m The point of attachment of ring E, ring F or ring G is at the carbon atom where ring E or ring G is fused to ring F. It is intended that ring G may be any available carbon or nitrogen atom, and The business owner understands.

[0069] [ka] is shown on ring E, ring F or ring G, [ka] The point of attachment of ring E, ring F or ring G is at the carbon atom where ring E or ring G is fused to ring F. It is intended that ring G may be any available carbon or nitrogen atom, and The business owner understands.

[0070] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the compound of formula I-ii: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -N(R), -Si(R), or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring E, ring F and ring G each independently represent a 6-membered aryl containing 0 to 3 nitrogen atoms, a 5-membered ~7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon or is a 5- to 7-membered saturated or are independently selected from partially unsaturated heterocyclyl, or nitrogen, oxygen, or sulfur A fused ring selected from 5-membered heteroaryls having 1 to 3 heteroatoms, wherein ring E, ring F and ring G are independently substituted with 1 to 2 oxo groups as needed. It is; m is 0, 1, 2, 3 or 4.

[0071] [ka] is shown on ring E, ring F or ring G, [ka] The point of attachment of is on ring E, ring F, or ring G, including the ring to which ring E or ring G is fused to ring F. It is intended that the atom may be any available carbon or nitrogen atom of the I understand.

[0072] -(R 2 ) m When the attachment point of -(R 2 ) m The point of attachment of ring E, ring F or ring G is at the carbon atom where ring E or ring G is fused to ring F. It is intended that ring G may be any available carbon or nitrogen atom, and The business owner understands.

[0073] In some embodiments, the compound of formula I-ii above is of formula I-ii' or formula I- ii”: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, L, Ring E, Ring F, Ring G, L, R 1 , R 2 , X 1 and m are each defined above. This is exactly as stated.

[0074] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the moiety has the formula I-jj: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is selected from a covalent bond, -CR2-, -NR-, -O-, -S- or -SiR2- is a bivalent moiety that is R 1 is absent or is hydrogen, deuterium, halogen, -CN, -OR, -SR, - S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2) OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3 , or C substituted as needed 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C( O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O) 2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR) (NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring E is a 6-membered aryl, nitrogen, oxygen, or sulfur independently selected from 1 to 4. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carbo 1 to 3 independently selected from cyclyl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl having a heteroatom of a 5-membered heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from heteroaryl; Ring H is a 7- to 9-membered, saturated or partially unsaturated carbocyclyl, or a boron, nitrogen a heteroatom having 1 to 3 heteroatoms independently selected from oxygen, silicon, or sulfur; and wherein ring E is a fused ring selected from a tetracyclyl ring and ...tetracyclyl ring, wherein ring E is a fused ring selected from a tetracyclyl ring and a tetracyclyl ring, Further substituted as necessary; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3 or 4.

[0075] [ka] is shown on ring E or ring H, [ka] The point of attachment of ring E or ring H may be any point on ring E or ring H, including the carbon atom to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be present. do.

[0076] -(R 2 ) m When the attachment points of -(R 2 ) m Combination of The point is any available carbon atom on ring E or ring H, including the carbon atoms to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be used.

[0077] [ka] are shown on ring E and ring H, [ka] The point of attachment of ring E or ring H may be any point on ring E or ring H, including the carbon atom to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be present. do.

[0078] In some embodiments, the compound of formula I-jj has formula I-jj' or formula I- jj”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring E, Ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each As defined in

[0079] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the moiety has the formula I-kk: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -N(R), -Si(R), or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring E is a 6-membered aryl, nitrogen, oxygen, or sulfur independently selected from 1 to 4. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carbo 1 to 3 independently selected from cyclyl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl having a heteroatom of a 5-membered heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from heteroaryl; Ring H is a 7- to 9-membered, saturated or partially unsaturated carbocyclyl, or a boron, nitrogen a heteroatom having 1 to 3 heteroatoms independently selected from oxygen, silicon, or sulfur; and wherein ring E is a fused ring selected from a tetracyclyl ring and ...tetracyclyl ring, wherein ring E is a fused ring selected from a tetracyclyl ring and a tetracyclyl ring, Further substituted as necessary; m is 0, 1, 2, 3 or 4.

[0080] [ka] is shown on ring E or ring H, [ka] The point of attachment of ring E or ring H may be any point on ring E or ring H, including the carbon atom to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be present. do.

[0081] -(R 2 ) m When the attachment points of -(R 2 ) m Combination of The point is any available carbon atom on ring E or ring H, including the carbon atoms to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be used.

[0082] [ka] are shown on ring E and ring H, [ka] The point of attachment of ring E or ring H may be any point on ring E or ring H, including the carbon atom to which ring E and ring H are fused. It is intended, and one of ordinary skill in the art will understand, that any available carbon or nitrogen atom may be present. do.

[0083] In some embodiments, the compound of formula I-kk has formula I-kk' or formula I- kk”: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring E, Ring H, L, R 1 , R 2 , X 1 and m are each defined above is.

[0084] In some embodiments, the present invention provides a compound in which Ring H is 1,3-dihydro-2H-1,4-dihydro azepin-2-one, thereby having the formula I-kk-1: [ka] or a pharmaceutically acceptable salt thereof. , where: IRAK, L, Tamaki E, X 1 , R 1 , R 2 and m are each as defined above .

[0085] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the compound of formula I-11: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O )R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is selected from a covalent bond, -CR2-, -NR-, -O-, -S- or -SiR2- is a bivalent moiety that is R 1 is absent or is hydrogen, deuterium, halogen, -CN, -OR, -SR, - S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2) OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3 , or C substituted as needed 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C( O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O) 2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR) (NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring I and ring J each independently comprise a 6-membered aryl, nitrogen, oxygen, and sulfur. 6-membered heteroaryl containing 1 to 4 selected heteroatoms, 5-membered to 7-membered saturated or or partially unsaturated carbocyclyl, independently of boron, nitrogen, oxygen, silicon or sulfur 5- to 7-membered saturated or partially unsaturated heteroatoms having 1 to 3 heteroatoms selected from the group tetracyclyl, or 1 to 4 heterocyclic groups independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from a 5-membered heteroaryl having a cycloalkyl group; Ring K is a 7- to 12-membered saturated or partially unsaturated carbocyclyl, or a boron, nitrogen, or having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur; A fused ring selected from heterocyclyl rings, wherein ring H is a fused ring selected from 1 to 2 oxo groups. with further substitution as necessary; L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; m is 0, 1, 2, 3 or 4.

[0086] [ka] are shown on ring I, ring J and ring K, [ka] The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0087] -(R 2 ) m When the attachment points of -(R 2 ) m The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0088] [ka] are shown on ring I, ring J and ring K, [ka] The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0089] In some embodiments, the compound of formula I-ll is of formula I-ll′ or I- ll”: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m, respectively. is as defined above.

[0090] In certain embodiments, the present invention provides compounds of formula I-mm: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -N(R), -Si(R), or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form the nitrogen plus 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur forming a 1-membered saturated, partially unsaturated, or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -O R, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N (R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring I and ring J each independently represent a 6-membered aryl, nitrogen, oxygen, or sulfur. 6-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of 5- to 7-membered saturated heteroaryls; or partially unsaturated carbocyclyl, independent of boron, nitrogen, oxygen, silicon or sulfur 5- to 7-membered saturated or partially unsaturated heteroatoms having 1 to 3 heteroatoms selected from the group consisting of heterocyclyl, or 1 to 4 hetero atoms independently selected from nitrogen, oxygen, or sulfur; a fused ring selected from a 5-membered heteroaryl having a heteroatom; Ring K is a 7- to 12-membered saturated or partially unsaturated carbocyclyl, or a boron, nitrogen, or having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur; A fused ring selected from heterocyclyl rings, wherein ring H is a fused ring selected from 1 to 2 oxo groups. with further substitution as necessary; m is 0, 1, 2, 3 or 4.

[0091] [ka] are shown on ring I, ring J and ring K, [ka] The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0092] -(R 2 ) m When the attachment points of -(R 2 ) m The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0093] [ka] are shown on ring I, ring J and ring K, [ka] The point of attachment of ring I, ring J, or ring K is at the carbon atom to which ring I, ring J, and ring K are fused. It is intended that ring K may be any available carbon or nitrogen atom, and The business owner understands.

[0094] In some embodiments, the compound of formula I-mm is of formula I-mm' or I- mm”: [ka] or a pharmaceutically acceptable salt thereof, wherein IRAK, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 and m are each defined above That's right.

[0095] In some embodiments, the present invention provides compounds wherein ring J is pyrrole, thereby providing compounds of formula I -mm-1: [ka] or a pharmaceutically acceptable salt thereof. , where: IRAK, L, Ring I, Ring K, X 1 , R 1 , R 2 and m are each defined above is.

[0096] As noted above, in another aspect, the present invention provides compounds of formula I-nn: [ka] or a pharmaceutically acceptable salt thereof, Ring M is, [ka] is selected from X 1 , X 6 and X 7 each independently represents a covalent bond, —CH—, —CHCF—, —S O2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C (O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 3 and X 5 each independently represents a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] is a trivalent moiety selected from Each R is independently hydrogen or an optionally substituted group, The selected group is C 1~6 1 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings having one to two heteroatoms, and 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or selected from: Two R groups on the same nitrogen, together with the atoms between them, form a nitrogen atom in addition to the nitrogen. 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. forming a saturated, partially unsaturated, or heteroaryl ring of Each R 3a are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, - OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O )R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O )R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP( O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -NP(O)R2 , -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P( -O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S( O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR , -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1~4 Is aliphatic; or R 7 and X 1 or X 3 These, together with the atoms between them, form a 5- to 7-membered saturated partially unsaturated, carbocyclic rings or rings consisting of atoms independently of boron, nitrogen, oxygen, silicon or sulfur forming a heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of: Two R on the same carbon 7 The groups, together with the atoms between them as needed, form 3 a fused spiro ring having 1 to 6 members or a ring independently selected from boron, nitrogen, oxygen, silicon, or sulfur; forming a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms selected from the group consisting of: Two R on adjacent carbon atoms 7 The groups are formed by combining atoms between them as needed. , 3- to 7-membered saturated, partially unsaturated, carbocyclic rings or rings containing boron, nitrogen, oxygen, silicon, or a heterocyclic ring having 1 to 3 heteroatoms independently selected from aryl, arylsulfur, or is 1 to 3 hetero atoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; 7-13 membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic rings containing atoms Forming; Ring D is a 6-membered aryl, 1 to 4 aryls independently selected from nitrogen, oxygen and sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; Selected from: L 1 is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogenated chain, wherein one to two methylene units of the chain are independently -O-, -C( O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R) optionally replaced by -, -S-, -S(O)2- or -(C)=CH- ; n is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4.

[0097] X, as defined above and described herein 1 , X 6 and X 7 Each of these is independent and covalent bonds, -CH2-, -C(R)2-, -C(O)-, -C(S)-, -CH( R)-, -CH(CF3)-, -P(O)(OR)-, -P(O)(R)-, -P(O) (NR2)-, -S(O)-, -S(O)2-, or [ka] is a divalent moiety selected from

[0098] In some embodiments, X 1 , X 6 and X 7 each of which is independently a covalent bond In some embodiments, X 1 , X 6 and X 7 each independently represents -CH2- In some embodiments, X 1 , X 6 and X 7 Each of the groups independently represents -CR 2-. In some embodiments, X 1 , X 6 and X 7 Each of the is independently - In some embodiments, X is C(O)—. 1 , X 6 and X 7 Each of these is independent. In some embodiments, X is -C(S)-. 1 , X 6 and X 7 Each of In some embodiments, X is -CH(R)-. 1 , X 6 and X 7 Each of X is independently -CH(CF3)-. 1 , X 6 and X 7 Each of is independently -P(O)(OR)-. X 1 , X 6 and X 7 Each of is independently -P(O)(R)-. In an embodiment, X 1 , X 6 and X 7 each independently is -P(O)NR- In some embodiments, X 1 , X 6 and X7 each independently represents -S(O)- In some embodiments, X 1 , X 6 and X 7 Each of the is independently -S( In some embodiments, X 1 , X 6 and X 7 Each of the , [ka] is.

[0099] In some embodiments, X 1 , X 6 and X 7 Each of these is illustrated in Table 1 below. are selected independently of one another.

[0100] X, as defined above and described herein 2 is a carbon atom, a nitrogen atom, or It is a silicon atom.

[0101] In some embodiments, X 2 is a carbon atom. , X 2 is a nitrogen atom. In some embodiments, X 2 is a silicon atom.

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

[0103] X, as defined above and described herein 3 are -CH2-, -CR2-, -NR-, -CF2-, -CHF-, -S-, -CH(R)-, -SiR2-, or - O-.

[0104] In some embodiments, X 3 and X 5 Each of is independently -CH2-. In some embodiments, X 3 and X 5 Each of is independently -CR2-. In some embodiments, X 3 and X 5 Each of is independently -NR-. In some embodiments, X 3 and X 5 Each of is independently -CF2-. In the embodiment, X 3 and X 5 Each of is independently -CHF-. In an embodiment, X 3 and X 5 Each of is independently -S-. In this state, X 3 and X 5 Each of is independently -CH(R)-. In terms of form, X 3 and X 5 Each of is independently -SiR2-. In terms of form, X 3 and X 5 Each of is independently -O-.

[0105] In some embodiments, X 3 and X 5 Each of the following is illustrated in Table 1: are selected independently from

[0106] X, as defined above and described herein 4 teeth, [ka] is a trivalent moiety selected from

[0107] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] is.

[0108] In some embodiments, X 4 is selected from those illustrated in Table 1 below.

[0109] R as defined above and described herein1 is hydrogen, deuterium, halide Rogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O )(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2 R, -Si(OH)R2, -SiR3, optionally substituted C 1~4 Is it aliphatic? , or R 1 and X 1 and or X 4 and together with the atoms between them, form a 5- to 7-membered and wherein the carbon atoms are independently selected from a saturated, partially unsaturated carbocyclic ring or nitrogen, oxygen, or sulfur. The heterocyclic ring may have 1 to 3 heteroatoms.

[0110] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is a halogen. In some embodiments, R 1 In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In embodiments, R 1 is -S(O)R. In some embodiments, R 1 teeth , -S(O)R. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is —P(O)(OR) 2 . In some embodiments, Hey, R 1 is -P(O)(NR2)OR. In some embodiments, R 1 is —P(O)(NR) . In some embodiments, R 1 is -Si(O H)R. In some embodiments, R 1 is -Si(OH)R2. In some embodiments, R 1 is -SiR. In some embodiments, R 1 is replaced by C 1~4 In some embodiments, R 1 and X 1 and or X 4 Together with the atoms between them, it forms a 5- to 7-membered saturated a partially unsaturated carbocyclic ring or one to two independently selected from nitrogen, oxygen, or sulfur; Forms a heterocyclic ring with three heteroatoms.

[0111] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0112] As defined above and described herein, each R independently represents hydrogen, deuterium, or an optionally substituted group, the optionally substituted group being C1 ~6 independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing 1 to 3 heteroatoms, and and 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. or two 5- or 6-membered heteroaryl rings on the same nitrogen; The R groups, together with the atoms between them, can contain nitrogen, boron, nitrogen, oxygen, ketone, and 4- to 7-membered alkyl groups having 0 to 3 heteroatoms independently selected from nitrogen and sulfur. It forms a saturated, partially unsaturated, or heteroaryl ring.

[0113] In some embodiments, R is hydrogen. , deuterium. In some embodiments, R is optionally substituted C 1~6 In some embodiments, R is an optionally substituted aliphatic group. In some embodiments, R is selected from the group consisting of boron, nitrogen, oxygen, silicon, and optionally substituted aryl groups having 1 to 3 heteroatoms independently selected from sulfur; In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring. is 1 to 4 hetero atoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; An optionally substituted 5- to 6-membered heteroaryl ring having several In this embodiment, two R groups on the same nitrogen, together with the atoms between them, In addition to nitrogen, 0 to 3 independently selected from boron, nitrogen, oxygen, silicon, and sulfur A 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring containing one heteroatom Form.

[0114] In some embodiments, R is selected from those depicted in Table 1 below.

[0115] R as defined above and described herein 2 and R 3a Each of the , hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -Si(OH )2R, -Si(OH)R2, -SR, -NR2, -SiR3, -S(O)2R, -S( O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C (O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O) NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR )2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O) OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, - NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0116] In some embodiments, R 2 and R 3a are independently hydrogen. In embodiments, R 2 and R 3a are independently deuterium. In the embodiment, R 2 and R 3a are independent, -R 6 In some embodiments, R 2 and R 3a is independently halogen. In some embodiments, R 2 and R 3a is independently -CN. In some embodiments, R 2 and R 3a is independently -NO. In some embodiments, R 2 and R 3a is German In some embodiments, R 2 and R 3a are independently - Si(OH)R. In some embodiments, R 2 and R3a is independent, In some embodiments, R 2 and R 3a is independent , -SR. In some embodiments, R 2 and R 3a are independently, -NR2 In some embodiments, R 2 and R 3a are independently -SiR3 In some embodiments, R 2 and R 3a are independently -S(O)R. In some embodiments, R 2 and R 3a are independently -S(O)2NR2 In some embodiments, R 2 and R 3a are independently -S(O)R. In some embodiments, R 2 and R 3a are independently -C(O)R. In some embodiments, R 2 and R 3a are independently -C(O)OR. In the embodiment, R 2 and R 3a are independently -C(O)NR2. In the embodiment, R 2 and R 3a are independently -C(O)N(R)OR. In some embodiments, R 2 and R 3a are independently -C(R)N(R)C(O )R. In some embodiments, R 2 and R 3a are independently -C(R)2 N(R)C(O)NR. In some embodiments, R 2 and R 3ais independent and -OC(O)R. In some embodiments, R 2 and R 3a is independent and -OC(O)NR. In some embodiments, R 2 and R 3a is independent and -OP(O)R. In some embodiments, R 2 and R 3a is independent and -OP(O)(OR). In some embodiments, R 2 and R 3a is independently -OP(O)(OR)NR. In some embodiments, R 2 oh Yobi R 3a are independently -OP(O)(NR)-. In some embodiments, Te, R 2 and R 3a is independently —N(R)C(O)OR. In R 2 and R 3a are independently -N(R)C(O)R. In terms of form, R 2 and R 3a are independently -N(R)C(O)NR2. In some embodiments, R 2 and R 3a are independently -NP(O)R2. In some embodiments, R 2 and R 3a are independently -N(R)P(O)(OR)2 In some embodiments, R 2 and R 3a are independently -N(R)P(O) (OR)NR. In some embodiments, R 2 and R 3a are independently - N(R)P(O)(NR). In some embodiments, R 2 and R 3a are independently —N(R)S(O)R.

[0117] In some embodiments, R 2 and R 3a are independently -OH. In the embodiment, R 2 and R 3a are independently -NH2. In this state, R 2 and R 3a is independently —CH 2 NH 2 . In R 2 and R 3a are independently -CH2NHCOMe. In terms of form, R 2 and R 3a are independently -CH2NHCONHMe. In some embodiments, R 2 and R 3a are independently -NHCOMe. In the embodiment, R 2 and R 3a are independently -NHCONHEt. In some embodiments, R 2 and R 3a are independently -SiMe3. In embodiments, R 2 and R 3a are independently -SiMe2OH. In embodiments, R 2 and R 3a are independently -SiMe(OH)2. In some embodiments, R 2 and R 3a is independent, [ka] In some embodiments, R 2 and R 3a are independently Br. In some embodiments, R 2 and R 3a are independently Cl. In this state, R 2 and R 3a is independently F. In some embodiments, R 2 and R 3a is independently Me. In some embodiments, R 2 and R 3 a is independently -NHMe. In some embodiments, R 2 and R 3a is German In some embodiments, R 2 and R 3a is independent , -NHCO2Et. In some embodiments, R 2 and R 3a is independent , -CN. In some embodiments, R 2 and R 3a are independently -CH2 In some embodiments, R 2 and R 3a are independently -NHCO2 In some embodiments, R 2 and R 3a independently, -CO2t In some embodiments, R 2 and R 3a is independently -OMe In some embodiments, R 2 and R 3a are independently -CF3.

[0118] In some embodiments, R 2 or R 3a is shown in Table 1 below. be selected.

[0119] R as defined above and described herein 3 is hydrogen, deuterium, halide Rogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2 NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O) NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP (O)(NR2)2, -OP(O)(OR)NR2, -N(R)C(O)R, -N(R) C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O )2NR2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -P (O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH )2R, -Si(OH)(R)2, or -Si(R)3.

[0120] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 is -OR. In the embodiment, R 3 is -NR2. In some embodiments, R 3 teeth, In some embodiments, R 3 is -S(O)2R. In the embodiment, R 3 is —S(O) 2 NR 2 . In some embodiments, , R 3 is -S(O)R. In some embodiments, R 3 is -C(O)R In some embodiments, R 3 is -C(O)OR. In this state, R 3 is —C(O)NR. In some embodiments, R 3 teeth, In some embodiments, R 3 is -OC(O)R In some embodiments, R 3 is -OC(O)NR2. In embodiments, R 3 is -OP(O)(OR). In some embodiments, Te, R 3 is -OP(O)(NR). In some embodiments, R 3 teeth, -OP(O)(OR)NR. In some embodiments, R 3 is -N(R) C(O)R. In some embodiments, R 3 is -N(R)C(O)OR In some embodiments, R 3 is -N(R)C(O)NR2. In the embodiment, R 3 is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R3 -N (R)P(O)(OR)NR. In some embodiments, R 3 is -P(O )(OR)2. In some embodiments, R 3 is -P(O)(NR2)OR In some embodiments, R 3 is -P(O)(NR2)2. In some embodiments, R 3 is —Si(OH)R. In some embodiments, Te, R 3 is —Si(OH)(R). In some embodiments, R 3 teeth,- Si(R)3.

[0121] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0122] In some embodiments, R 3 is selected from those illustrated in Table 1.

[0123] As defined above and described herein, each R 4 are independently hydrogen, deuterated Sodium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O) 2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O) NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C (O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2 R, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2 is.

[0124] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 -R 6 In some embodiments, R 4 are halogens. In the embodiment, R 4 is -CN. In some embodiments, R 4 teeth,- In some embodiments, R 4 is -OR. In this state, R 4 is -SR. In some embodiments, R 4 is -NR2 In some embodiments, R 4 is -S(O)R. In this state, R 4 is —S(O)NR. In some embodiments, R 4 teeth , -S(O)R. In some embodiments, R 4 is -C(O)R. In some embodiments, R 4 is —C(O)OR. In some embodiments, Te, R 4 is —C(O)NR. In some embodiments, R 4 is -C(O )N(R)OR. In some embodiments, R 4 is -OC(O)R. In some embodiments, R 4 is —OC(O)NR 2 . In R 4 is —N(R)C(O)OR. In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is -N(R)C (O)NR2. In some embodiments, R 4 is -N(R)S(O)R In some embodiments, R 4 is -P(O)(OR)2. In embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0125] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0126] In some embodiments, R 4 is selected from those illustrated in Table 1.

[0127] R as defined above and described herein 5 are hydrogen, deuterium, and C replaced as needed 1~4 It is aliphatic, or -CN.

[0128] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is replaced as needed C 1~4 In some embodiments, R 5 is -CN.

[0129] In some embodiments, R 5is selected from those illustrated in Table 1.

[0130] As defined above and described herein, each R 6 independently, C 1~6 aliphatic , 1 to 3 independently selected from phenyl, boron, nitrogen, oxygen, silicon, and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing heteroatoms of , having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, silicon, and sulfur; and optionally substituted groups selected from 5- to 6-membered heteroaryl rings.

[0131] In some embodiments, R 6 is replaced by C 1~6 It is aliphatic In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is independently derived from boron, nitrogen, oxygen, silicon and sulfur. Optionally substituted 4- to 7-membered saturated heteroatoms with 1 to 3 selected heteroatoms or a partially unsaturated heterocyclic ring. In some embodiments, R 6 is boron, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, silicon, and sulfur; and optionally substituted 5- to 6-membered heteroaryl rings.

[0132] In some embodiments, R 6 is selected from those illustrated in Table 1.

[0133] As generally defined above, each R 7 are independently hydrogen, deuterium, halogen , -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O) (R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2 , -Si(OH)R2, -Si(OH)2R, -SiR3 or optionally substituted TaC 1~4 Aliphatic or R 1 and X 1 Or X 3 The original text is based on the original text. Together with the aryl, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or a ring containing boron, nitrogen, or a complex having 1 to 3 heteroatoms independently selected from oxygen, silicon, or sulfur; Form a monocyclic ring or two R on the same carbon 7 The group must be connected to the atoms between them. Optionally, together, they form a 3- to 6-membered spiro-fused ring or a ring containing boron, nitrogen, oxygen, silicon, A 4- to 7-membered complex having 1 to 2 heteroatoms independently selected from nitrogen or sulfur. Two R on adjacent carbon atoms form a monocyclic ring or 7 The group is the atom between these and optionally together form a 3- to 7-membered saturated, partially unsaturated carbocyclic ring or hydroxyl group. 1 to 3 heteroatoms independently selected from uran, nitrogen, oxygen, silicon, or sulfur or a heterocyclic ring having an atom independently selected from boron, nitrogen, oxygen, silicon, or sulfur; 7-13 membered saturated, partially unsaturated, bridged heterocycles containing 1-3 heteroatoms selected from the group consisting of The heterocyclic ring forms a heterocyclic or spiro heterocyclic ring.

[0134] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -SR. In embodiments, R 7 is -S(O)R. In some embodiments, R 7 teeth , -S(O)R. In some embodiments, R 7 is -NR2. In some embodiments, R 7 , -Si(R)3. In some embodiments, R 7 is -P(O)(R). In some embodiments, R 7 is -P(O) (OR)2. In some embodiments, R 7 is -P(O)(NR2)OR In some embodiments, R 7 is -P(O)(NR2)2. In the embodiment, R 7 is —Si(OH)R 2 . In some embodiments, , R 7 is —Si(OH)R. In some embodiments, R 7 If necessary, Substituted C 1~4 In some embodiments, R 7 and X 1 And again is X 3 These, together with the atoms between them, form a 5- to 7-membered saturated, partially unsaturated a carbocyclic ring or one to four atoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; In some embodiments, the heterocyclic ring has three heteroatoms. Two R on prime 7The group, together with the atoms between them as needed, can form a 3- to 6-membered or one independently selected from boron, nitrogen, oxygen, silicon, or sulfur In some embodiments, the heterocyclic ring has 4 to 7 members and 2 heteroatoms. In the formula, two R on adjacent carbon atoms 7 The group can be formed by adding atoms between them as needed. and a 3- to 7-membered saturated or partially unsaturated carbocyclic ring or a ring containing boron, nitrogen, oxygen, ketone, or a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen or sulfur; In some embodiments, two R on adjacent carbon atoms 7 The group is between these Independently of boron, nitrogen, oxygen, silicon, or sulfur, optionally in combination with certain atoms 7-13 membered saturated, partially unsaturated bridges with 1-3 heteroatoms selected as Forming a heterocyclic or spiroheterocyclic ring.

[0135] In some embodiments, R 7 represents hydrogen, halogen, -CN, -OR, -NR2, or C 1~4 In some embodiments, R 7 is hydrogen, Halogen, -CN, or C 1~4 In some embodiments, Te, R 7 is fluoro. In some embodiments, two R on the same carbon 7 base may be joined with atoms between them as needed to form a 3- or 4-membered spiro-fused ring. Form.

[0136] In some embodiments, R 7 is selected from those illustrated in Table 1 below.

[0137] As defined above and described herein, ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from:

[0138] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0139] In some embodiments, ring A is selected from those depicted in Table 1 below.

[0140] As defined above and described herein, Ring B is a 6-membered aryl, nitrogen, acid A six-membered heteroaryl containing one to four heteroatoms independently selected from nitrogen or sulfur. aryl, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, ketone 5- to 7-membered alkyl groups having 1 to 3 heteroatoms independently selected from nitrogen and sulfur saturated or partially unsaturated heterocyclyl, or independently of nitrogen, oxygen or sulfur A fused ring selected from 5-membered heteroaryls having 1 to 4 selected heteroatoms. is.

[0141] In some embodiments, Ring B is a fused 6-membered aryl. In embodiments, ring B contains 1 to 4 atoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the ring is a fused 6-membered heteroaryl containing a heteroatom. B is a fused 5- to 7-membered saturated or partially unsaturated carbocyclyl. In an embodiment, ring B is independently selected from boron, nitrogen, oxygen, silicon, or sulfur. Condensed 5- to 7-membered saturated or partially saturated heterocyclic rings containing 1 to 3 heteroatoms In some embodiments, ring B is boron, nitrogen, oxygen, silicon or or sulfur, It is aryl.

[0142] 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] In some embodiments, ring B is [ka] is.

[0143] In some embodiments, each ring B is [ka] In some embodiments, each ring B is: [ka] In some embodiments, each ring B is: [ka] In some embodiments, each ring B is: [ka] In some embodiments, ring B is [ka] is.

[0144] 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] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0145] 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] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0146] 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] In some embodiments, ring B is [ka] is.

[0147] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0148] As defined above and described herein, ring C is [ka] is a monocyclic or bicyclic ring selected from:

[0149] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0150] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0151] In some embodiments, ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0152] In some embodiments, ring C is selected from those depicted in Table 1 below.

[0153] As defined above and described herein, Ring D is a 6-membered aryl, nitrogen, acid A six-membered heteroaryl containing one to four heteroatoms independently selected from nitrogen or sulfur. aryl, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, ketone 5- to 7-membered alkyl groups having 1 to 3 heteroatoms independently selected from nitrogen and sulfur saturated or partially unsaturated heterocyclyl, or independently of nitrogen, oxygen or sulfur A ring selected from 5-membered heteroaryls having 1 to 4 selected heteroatoms. do.

[0154] In some embodiments, ring D is a 6-membered aryl. wherein ring D is 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; In some embodiments, ring D is a 6-membered heteroaryl including: In some embodiments, ring D is a saturated or partially unsaturated carbocyclyl of the formula: 1 to 3 heteroatoms independently selected from the group consisting of boron, nitrogen, oxygen, silicon, and sulfur; and a 5- to 7-membered saturated or partially saturated heterocyclyl having 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, In this embodiment, ring D is one independently selected from boron, nitrogen, oxygen, silicon, and sulfur. It is a 5-membered heteroaryl having 1 to 4 heteroatoms.

[0155] In some embodiments, ring D is selected from those depicted in Table 1 below.

[0156] As defined above and described herein, each of rings E, F, and G independently and 1 to 4 aryl groups independently selected from 6-membered aryl, nitrogen, oxygen, or sulfur. 6-membered heteroaryl containing heteroatoms, 5-membered to 7-membered saturated or partially unsaturated carboxyl 1 to 3 independently selected from kryl, boron, nitrogen, oxygen, silicon, and sulfur 5- to 7-membered saturated or partially unsaturated heterocyclyl containing a heteroatom or nitrogen a 5-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen and sulfur; wherein ring E, ring F, and ring G are fused rings selected from aryl; Optionally substituted with up to two oxo groups.

[0157] In some embodiments, each of ring E, ring F, and ring G is independently a 6-membered aryl. In some embodiments, ring E, ring F, and ring G are fused rings selected from the group consisting of: 1 to 4 heteroatoms, each independently selected from nitrogen, oxygen, or sulfur In some embodiments, the fused ring is selected from a 6-membered heteroaryl, including , ring E, ring F and ring G each independently represent a 5- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ring E, ring F, and ring H are fused rings selected from cyclyl. Each ring G is independently selected from boron, nitrogen, oxygen, silicon, or sulfur. 5- to 7-membered saturated or partially unsaturated heterocyclyl containing 1 to 3 heteroatoms In some embodiments, each of ring E, ring F, and ring G is a fused ring selected from the group consisting of: each independently have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the fused ring is selected from a 5-membered heteroaryl. Ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups. .

[0158] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is: [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] is.

[0159] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] is.

[0160] In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is.

[0161] In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is.

[0162] In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is. In some embodiments, each of ring E and ring G is independently: [ka] is.

[0163] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] is.

[0164] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] In some embodiments, ring E, ring F and ring G are [ka] is.

[0165] In some embodiments, ring E, ring F, and ring G are those depicted in Table 1 below. is selected from.

[0166] As defined above and described herein, ring H is a 7- to 9-membered, saturated or is a partially unsaturated carbocyclyl ring or is independently selected from boron, nitrogen, oxygen, silicon, and sulfur atoms. and a heterocyclyl ring having 1 to 3 heteroatoms selected from the group consisting of: wherein ring E is optionally further substituted with 1 to 2 oxo groups.

[0167] In some embodiments, ring H is a 7- to 9-membered saturated or partially unsaturated cyclic ring. a bocyclyl ring or one independently selected from boron, nitrogen, oxygen, silicon, or sulfur; A ring selected from heterocyclyl rings having up to 3 heteroatoms, wherein ring H is It is further substituted with 1 to 2 oxo groups as needed.

[0168] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] is.

[0169] In some embodiments, ring H is selected from those depicted in Table 1 below.

[0170] In some embodiments, ring E and ring H are [ka] is.

[0171] As defined above and described herein, each of ring I and ring J is independently 6-membered aryl, 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 6-membered heteroaryl containing 5- to 7-membered saturated or partially unsaturated carbocyclyl , 1 to 3 hetero atoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; 5- to 7-membered saturated or partially unsaturated heterocyclyl containing atoms, or nitrogen, oxygen or sulfur; It is a fused ring selected from the group consisting of aryl, arylsulfonyl ...

[0172] In some embodiments, each of ring I and ring J is independently a 6-membered aryl. In some embodiments, each of ring I and ring J is independently nitrogen, oxygen, or is a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from sulfur; In some embodiments, each of rings I and J is independently a 5- to 7-membered saturated or or a partially unsaturated carbocyclyl. In some embodiments, ring I and ring J are each independently represents one atom selected from boron, nitrogen, oxygen, silicon, or sulfur. 5- to 7-membered saturated or partially unsaturated heterocyclyl having up to 3 heteroatoms In some embodiments, each of ring I and ring J independently represents a nitrogen, oxygen, or sulfur atom. and a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from .

[0173] In some embodiments, each of ring I and ring J is independently: [ka] In some embodiments, ring I and ring J are each independently: [ka] In some embodiments, ring I and ring J are each independently: [ka] In some embodiments, ring I and ring J are each independently: [ka] In some embodiments, ring I and ring J are each independently: [ka] is.

[0174] In some embodiments, ring I and ring J are independently: [ka] In some embodiments, ring I and ring J are independently: [ka] In some embodiments, ring I and ring J are independently: [ka] is.

[0175] In some embodiments, ring I and ring J are selected from those depicted in Table 1 below. It is selected.

[0176] As defined above and described herein, ring K is a 7- to 12-membered, saturated or unsaturated ring. Partially unsaturated carbocyclyl or aryl independently of boron, nitrogen, oxygen, silicon or sulfur and a fused ring selected from heterocyclyl having 1 to 3 heteroatoms selected from wherein ring H is optionally further substituted with 1 to 2 oxo groups.

[0177] In some embodiments, ring K is a 7- to 12-membered saturated or partially unsaturated carbo In some embodiments, ring K is a fused ring selected from boron, having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur; It is a 7- to 12-membered saturated or partially unsaturated heterocyclyl ring. wherein ring K is optionally further substituted with 1 to 2 oxo groups.

[0178] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] is.

[0179] In some embodiments, ring K is selected from those depicted in Table 1 below.

[0180] In some embodiments, ring I, ring J and ring K are [ka] is.

[0181] As defined above and described herein, ring M is [ka] [ka] is selected from.

[0182] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] is.

[0183] In some embodiments, ring M is selected from those depicted in Table 1 below.

[0184] As defined above and described herein, L 1 is a covalent bond, or C 1~3 of a divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one of the chains ~Two methylene units are independently -O-, -C(O)-, -C(S)-, -C(R)2 -, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2- or - (C)=CH- is optionally replaced.

[0185] In some embodiments, L 1 is a covalent bond. , L 1 is C 1~3 In some embodiments, L 1 is -CH2- In some embodiments, L 1 is -C(D)(H)-. In the embodiment, L 1 is -C(D)2-. In some embodiments, L 1 teeth , -CH2CH2-. In some embodiments, L 1 is -NR-. In some embodiments, L 1 is -CHNR-. In some embodiments, L 1 is —O—. In some embodiments, L 1 is -CH2O- In some embodiments, L 1 is -S-. In some embodiments, L 1is -OC(O)-. In some embodiments, L 1 is -C(O)O- In some embodiments, L 1 is -C(O)-. In this state, L 1 is —S(O)—. In some embodiments, L 1 -S (O)2-. In some embodiments, L 1 is -NRS(O)2-. In some embodiments, L 1 is -S(O)NR-. In L 1 is -NRC(O)-. In some embodiments, L 1 teeth,- C(O)NR-.

[0186] In some embodiments, ring L 1 is selected from those illustrated in Table 1 below .

[0187] As defined above and described herein, [ka] is a single or double bond.

[0188] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0189] In some embodiments, [ka] is selected from those illustrated in Table 1 below.

[0190] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, , 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0191] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is In some embodiments, m is 3. In some embodiments, m is 4. m is 5. In some embodiments, m is 6. In some embodiments, In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 1 It is 6.

[0192] In some embodiments, m is selected from those depicted in Table 1 below.

[0193] As defined above and described herein, n is 0, 1, 2, 3, or 4. do.

[0194] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is In some embodiments, n is 3. In some embodiments, n is 4.

[0195] In some embodiments, n is selected from those depicted in Table 1 below.

[0196] As defined above and described herein, p is 0 or 1.

[0197] In some embodiments, p is 0. In some embodiments, p is 1. be.

[0198] In some embodiments, p is selected from those depicted in Table 1 below.

[0199] As defined above and described herein, q is 0, 1, 2, 3, or 4. do.

[0200] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is In some embodiments, q is 3. In some embodiments, q is 4.

[0201] In some embodiments, q is selected from those depicted in Table 1 below.

[0202] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0203] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0204] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0205] In some embodiments, the LBM is selected from those in Table 1 below.

[0206] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and ring Q is benzo and a single R x is -OR and X is cyclohexane as shown. and xyl of formula Ie-4: [ka] or a pharmaceutically acceptable salt thereof. where LBM X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A and m, L, and the L in the IRAK part x , ring P, ring T, R, R x , R y , each of x and y is independently Both singly and in combination, as defined above and described in embodiments herein. This is as can be seen.

[0207] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] wherein ring Q and ring P form an indazole ring, and a single R x is -OR and X is and cyclohexyl as defined above, and formula Ie-5: [ka] or a pharmaceutically acceptable salt thereof. where LBM X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , ring A and m, L, and the L in the IRAK part x , ring T, R, R x , R y , x and y each independently and in combination as defined above and as described in the embodiments herein. This is the case.

[0208] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and ring Q is benzo and a single R x is -OR and X is cyclohexane as shown. and xyl of formula Ie-6: [ka] or a pharmaceutically acceptable salt thereof. where LBM X 1 , R 1 , R 2 , rings A and m, L, and IRAK part L per minute x , ring P, ring T, R, R x , R y , x and y, alone and in combination and wherein both are as defined above and described in embodiments herein.

[0209] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] wherein ring Q and ring P form an indazole ring, and a single R x is -OR and X is and cyclohexyl as defined above, and formula Ie-7: [ka] or a pharmaceutically acceptable salt thereof. where LBM X 1 , R 1 , R 2 , rings A and m, L, and IRAK part L per minute x , ring T, R, R x , Ry , x and y, alone and in combination, Both are as defined above and described in the embodiments herein.

[0210] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and L is [ka] and ring Q is benzo and a single R x is -OR and X is cyclohexane as shown. and xyl of formula Ie-8: [ka] or a pharmaceutically acceptable salt thereof, provides compound I'-a, where X of LBM 1 , R 1 , R 2 , ring A and m, then and the L of the IRAK part x , ring P, ring T, R, R x , R y , x and y each independently and in combination as defined above and described in embodiments herein. That's right.

[0211] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and L is [ka] wherein ring Q and ring P form an indazole ring, and a single R x is -OR and X is and cyclohexyl as defined above, and formula Ie-9: [ka] or a pharmaceutically acceptable salt thereof, provides compound I'-a, where X of LBM 1 , R 1 , R 2 , ring A and m, then and the L of the IRAK part x , ring T, R, R x , R y , x and y may be used singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0212] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and ring Q is benzo and a single R x is -OR and X is cyclohexane as shown. and xyl of formula Ie-10: [ka] or a pharmaceutically acceptable salt thereof, provides compound I'-a, where R of LBM 2 and m, L, and IRAK parts L per minute x , ring P, ring T, R, R x , R y , x and y, alone and in combination and wherein both are as defined above and described in embodiments herein.

[0213] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] wherein ring Q and ring P form an indazole ring, and a single R x is -OR and X is and cyclohexyl as defined above, and formula Ie-11: [ka] or a pharmaceutically acceptable salt thereof, provides compound I'-a, where R of LBM 2 and m, L, and IRAK parts L per minute x , ring T, R, R x , R y , x and y, alone and in combination, Both are as defined above and described in the embodiments herein.

[0214] In some embodiments, LBM is prepared as described in M. Toure, CM Crew s, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO2017 / 176708, US2017 / 0281 784, WO2017 / 161119, WO2017 / 176957, WO2017 / 1 76958, WO2015 / 160845, US2015 / 0291562, WO201 6 / 197032, WO2016 / 105518, US2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO2013 / 106643, U S2014 / 0356322, WO2002 / 020740, US2002 / 00680 63, WO2012 / 078559, US2014 / 0302523, WO2012 / 0 03281, US2013 / 0190340, US2016 / 0022642, WO20 14 / 063061, US2015 / 0274738, WO2016 / 118666, U S2016 / 0214972, WO2016 / 149668, US2016 / 02726 39, WO2016 / 169989, US2018 / 0118733, WO2016 / 1 97114, US2018 / 0147202, WO2017 / 011371, US201 7 / 0008904, WO2017 / 011590, US2017 / 0037004, W O2017 / 079267, US2017 / 0121321, WO2017 / 11747 3, WO2017 / 117474, WO2013 / 106646, WO2014 / 108 452, WO2017 / 197036, US2019 / 0076540, WO2017 / 197046, US2019 / 0076542, WO2017 / 197051, US20 19 / 0076539, WO2017 / 197055, US2019 / 0076541 and and E3 linkers known to those skilled in the art, including those described in WO2017 / 197056. and gauze ligands, each of which is incorporated herein by reference in its entirety.

[0215] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). are linking moieties, whereby the groups represented by the formulae I-oo-1, I-oo-2, I-oo- 3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, Io o-9 or I-oo-10: [ka] or compounds of the formula I-oo'-1, I-oo'-2, I-oo'-3, I -oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I -oo'-9 or I-oo'-10: [ka] or compounds of the formula I-oo"-1, I-oo"-2, I-oo"-3, I -oo”-4, I-oo”-5, I-oo”-6, I-oo”-7, I-oo”-8, I -oo”-9 or I-oo”-10: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. where variable [ka] , X, X1, X2, Y, R1, R3, R3', R4, R5, t, m and n are each As defined and described in US2017 / 007612 and US2018 / 0134684 and the entirety of each of which is incorporated herein by reference.

[0216] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). and a linking moiety, whereby the formula I-pp-1, I-pp-2, I-pp- 3, I-pp-4, I-pp-5 or I-pp-6: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. There are variables A, G, G', Q1, Q2, Q3, Q4, R, R', W, X, Y, Z, [ka] and n are each independently selected from the group consisting of aryl, aryloxy ... As defined and described herein, each of which is incorporated herein by reference in its entirety. It is used.

[0217] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0218] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0219] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0220] In some embodiments, the LBM is selected from those in Table 1 below.

[0221] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and amides of formula Ii-1: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R, R x , R y , ring P, ring Q, ring T, [ka] Each of x and y, both alone and in combination, is defined above, As described in the embodiments herein.

[0222] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and a thioamide of formula Ii-2: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R, R x , R y , ring P, ring Q, ring T, [ka] Each of x, x, and y, both alone and in combination, is as defined above. as defined and as described in the embodiments herein.

[0223] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and 1,2,4-triazoles of formula Ii-3: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0224] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and 1,3,4-oxadiazoles of formula Ii-4: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0225] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and oxazoles of formula Ii-5: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0226] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown thiazoles of formula Ii-6: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0227] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (LBM) comprising administering to a patient a therapeutically effective amount of thalidomide, the method ... x is shown and imidazoles of formula Ii-7: [ka] or a pharmaceutically acceptable salt thereof. where L, X, R x , R y , ring P, ring Q, ring T, [ka] , x, and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0228] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a benzoxazole ring as shown to form a compound of formula Ij-1: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0229] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a benzothiazole ring as shown to form a compound of formula Ij-2: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0230] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms an indazole ring as shown to form a compound of formula Ij-3: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0231] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a pyrazolopyridine ring as shown to form a compound of formula Ij-4: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0232] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms an imidazole ring, and R x As shown [ka] and having formula Ik-1: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R, Ry , the ring T, and y are each both in combination as defined above and as described in embodiments herein is.

[0233] In some embodiments, the present invention provides a method for treating LBM comprising administering to a subject the method of the present invention, wherein the LBM is thalidomide or [ka] and the ring Q is [ka] and a single R x is —OR, X is cyclohexyl as shown, and -k-2 or Ik-3: [ka] or a pharmaceutically acceptable salt thereof. wherein L is as defined above and as described in embodiments herein. can be, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same carbon or nitrogen atom may be combined with the atoms between them as needed. In addition to carbon or nitrogen, 0 to 3 independently selected from nitrogen, oxygen, and sulfur Forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring containing a heteroatom ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring P is a benzo, 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen, acid a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen and sulfur; is a 5-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally fused ring independently selected from 6-membered heteroaryl rings, wherein ring P is optionally substituted with 1 to 2 oxo groups; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; L xis a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogen fluoride chain, wherein one to two methylene units of said chain are independently -Cy x -,- O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - Replaced as needed by NR-, -N=CR-, -CR=CR- or -S(O)2- where -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR -R is R x or R y In combination with 4- to 7-membered saturated or partially unsaturated carbon a heterocyclic ring or a ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; can form a heterocyclic ring having -Cy x - represents 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having Five-membered heteroatoms having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from -Cy x -teeth, optionally substituted with 1 to 2 oxo groups; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0234] In certain embodiments, the present invention provides L x is an amide, ring P is pyrazolyl, Ring T is pyridyl, R is Me, and R y is -CF3, provides the compound Ik-3.

[0235] In some embodiments, the present invention provides a method for treating LBM comprising administering to a subject the method of the present invention, wherein the LBM is thalidomide or [ka] wherein ring P and ring Q form an imidazole ring, and a single R x is -OR and X is and cyclohexyl as defined above, and of formula Ik-4 or Ik-5: [ka] or a pharmaceutically acceptable salt thereof. wherein L is as defined above and as described in embodiments herein. can be, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's XThe groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same carbon or nitrogen atom may be combined with the atoms between them as needed. In addition to carbon or nitrogen, 0 to 3 independently selected from nitrogen, oxygen and sulfur Forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring containing a heteroatom ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; L x is a covalent bond, or C 1~3 Divalent straight or branched chain saturated or unsaturated carbon a hydrogen fluoride chain, wherein one to two methylene units of said chain are independently -Cy x -,- O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - Replaced as needed by NR-, -N=CR-, -CR=CR- or -S(O)2- where -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR -R is R x or R y In combination with 4- to 7-membered saturated or partially unsaturated carbon a heterocyclic ring or a ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; can form a heterocyclic ring having -Cy x- represents 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having Five-membered heteroatoms having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted ring selected from -Cy x -teeth, optionally substituted with 1 to 2 oxo groups; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0236] In certain embodiments, the present invention provides L x is an amide, Ring T is pyridyl, and R is Me and R y is —CF3. To provide.

[0237] In some embodiments, the present invention provides a method for treating LBM comprising administering to a subject the method of the present invention, wherein the LBM is thalidomide or [ka] and the ring Q is [ka] and a, L x is an amide and has a single R x is -OR and X is SiC as shown and hexyl of formula Ik-6 or Ik-7: [ka] or a pharmaceutically acceptable salt thereof. wherein L is as defined above and as described in embodiments herein. can be, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same carbon or nitrogen atom may be combined with the atoms between them as needed. In addition to carbon or nitrogen, 0 to 3 independently selected from nitrogen, oxygen and sulfur Forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring containing a heteroatom ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring P is a benzo, 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen, acid a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen and sulfur, is a 5-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally fused ring independently selected from 6-membered heteroaryl rings, wherein ring P is optionally substituted with 1 to 2 oxo groups; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0238] In certain embodiments, the present invention provides compounds wherein ring P is pyrazolyl and ring T is pyridyl. , R is Me and R y is —CF3, to provide.

[0239] In some embodiments, the present invention provides a method for treating LBM comprising administering to a subject the method of the present invention, wherein the LBM is thalidomide or [ka] wherein ring P and ring Q form an imidazole ring, and L x is an amide and has a single R x but -OR, and X is cyclohexyl as shown, and formula Ik-8 or Ik -9: [ka] or a pharmaceutically acceptable salt thereof. wherein L is as defined above and as described in embodiments herein. can be, Each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same oxygen or nitrogen atom may be combined with the atoms between them as needed. In addition to oxygen or nitrogen, 0 to 3 independently selected from nitrogen, oxygen, and sulfur Forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring containing a heteroatom ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring T is phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or nitrogen; Heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen and sulfur, or or a five-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 to 9-membered monocyclic or bicyclic heteroaryl rings, wherein Ring T is further selected from the group consisting of: optionally substituted with one to two oxo groups; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0240] In certain embodiments, the present invention provides a compound wherein Ring T is pyridyl, R is Me, and R y but The compound of formula Ik-8 or Ik-9 above is provided, wherein:

[0241] In some embodiments, the present invention provides a method for treating LBM comprising administering to a subject the method of the present invention, wherein the LBM is thalidomide or [ka] wherein ring P and ring Q form an imidazole ring, ring T is pyridyl, and L x Gaami is a single R x is -OR, X is cyclohexyl as shown, and Ik-10 or Ik-11: [ka] or a pharmaceutically acceptable salt thereof. wherein L is as defined above and as described in embodiments herein. can be, Each R x are independently hydrogen, deuterium, R z, halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2 , -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C (O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(O)NR2, -N(R)S(O)2R, -N + (O - )R2, -OP(O)R2 , -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or [ka] or 2 R's X The groups, optionally taken together, are independently selected from nitrogen, oxygen, or sulfur. Optionally substituted 5- to 6-membered heterocyclic groups having 0 to 3 heteroatoms selected from forming a saturated ring or an aryl-fused ring, Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 one independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur 3- to 7-membered saturated or partially unsaturated heterocyclic rings containing up to two heteroatoms, and nitrogen 5- to 6-membered alkyl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a heteroaryl ring selected from: Two R groups on the same carbon or nitrogen atom may be combined with the atoms between them as needed. In addition to carbon or nitrogen, 0 to 3 independently selected from nitrogen, oxygen and sulfur Forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring containing a heteroatom ; Each R y are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R , -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP (O)(OR)NR2, -OP(O)(NR2)2, -SiR3, -SF5, or [ka] is; Each R z independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; each x is 0, 1, 2, 3, or 4; Each y is 0, 1, 2, 3, or 4.

[0242] In certain embodiments, the present invention provides a compound wherein R is Me and R y is -CF3, Ik-10 or Ik-11 compounds are provided.

[0243] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and the ring Q is [ka] and a single R x is —OR, X is cyclohexyl as shown, and Formula I -k-12: [ka] or a pharmaceutically acceptable salt thereof. where the variable [ka] , Y, R1, R3, R3', R4, R5, t, m, n, ring P, ring T, L, L x , R x , R y , x and y, both alone and in combination, are defined above; As described in the embodiments herein.

[0244] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] and the ring Q is [ka] and a single R xis —OR, X is cyclohexyl as shown, and -k-13: [ka] or a pharmaceutically acceptable salt thereof. where variable X 1 , X 2 , X 3 , R 1 , R 2 , ring A, m, ring P, ring T, L, L x , R x , R y , x, and y, both alone and in combination, As defined above and described in the embodiments herein.

[0245] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] wherein ring P and ring Q form an imidazole ring, and a single R x is -OR and X is and cyclohexyl as shown in formula Ik-14: [ka] or a pharmaceutically acceptable salt thereof. where the variable [ka] , Y, R1, R3, R3', R4, R5, t, m, n, ring T, L, L x , R x , R y , x and y, both alone and in combination, are defined above and As described in the embodiments herein.

[0246] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a subject the method ... [ka] wherein ring P and ring Q form an imidazole ring, and a single R x is -OR and X is and cyclohexyl as shown in formula Ik-15: [ka] or a pharmaceutically acceptable salt thereof. where variable X 1 , X 2 , X 3 , R 1 , R 2 , ring A, m, ring T, L, L x , R x , R y Each of x, x, and y, both alone and in combination, is As defined and described in the embodiments herein.

[0247] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms an imidazole ring, and ring T is cyclohexyl as shown, and formula II -1: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , Ry Each of x, x, and y may be used singly or in combination. both in combination as defined above and as described in embodiments herein is.

[0248] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a 4,5,6,7-tetrahydro-2H-indazole ring as shown, Formula II-2: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0249] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms an isoindolin-1-one ring as shown to form a compound of formula Il-3: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0250] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a quinoline ring as shown to form a compound of formula Im-1: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0251] In some embodiments, the present invention provides a compound in which the LBM is thalidomide and the ring P and ring Q forms a 2H-thieno[2,3-c]pyrazole ring as shown to form a compound of formula Im-2 : [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0252] In some embodiments, the present invention relates to a compound in which the LBM is thalidomide and the ring P is pyridinium. and ring Q is phenyl as shown, and has the formula In-1: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0253] In some embodiments, the present invention relates to a compound in which the LBM is thalidomide and the ring P is a pyrazolone. ring Q is phenyl as shown, and has the formula In-2: [ka] or a pharmaceutically acceptable salt thereof. where L, L x , X, R x , R y , each of the rings T, x, and y is independently and in combination as defined above and described in embodiments herein. That's right.

[0254] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the moiety has the formula I-qq-1, I-qq-2 or Iq Q-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein; and Variable R 1 , R 2 , R 4 , R5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 ,X, [ka] and n are each as defined in WO2017 / 197051, and the whole is , which is incorporated herein by reference; and [ka] is R 1 is bonded to R 1 and R 2 or R 12 R of the binding site of 17 is as defined in WO2017 / 197051, and as a result Fruit, [ka] But this R 12 Occupy the position of the substituent.

[0255] In some embodiments, the present invention provides a method for the production of ubiquitin-binding proteins (LBMs) that bind to E3 ubiquitin ligases (e.g., cerebrin). I-rr-1, I-rr-2, and Ir-rr-3 are bonded moieties, which are represented by the formulas I-rr-1, I-rr-2, and Ir-rr-4, respectively. r-3, or I-rr-4: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein; and Variable R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 ,X, [ka] and n are each as defined in WO 2018 / 237026, is incorporated herein by reference in its entirety; and [ka] is R as defined in WO 2018 / 237026 1 or R 16 To, R 12 of It binds at the binding site, resulting in [ka] But this R 12 Occupy the position of the substituent.

[0256] In some embodiments, the present invention provides a method for the production of ubiquitin-binding proteins (LBMs) that bind to E3 ubiquitin ligases (e.g., cerebrin). I-ss-1 or I-ss-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein; and Variable R 1 , R 14 , and R 16Each of the following is defined in WO 2018 / 237026: No. 6,299,499, the entirety of each of which is incorporated herein by reference; and [ka] is R as defined in WO 2018 / 237026 1 or R 16 To, R 12 of It binds at the binding site, resulting in [ka] But this R 12 Occupy the position of the substituent.

[0257] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the formula I-tt-1, I-tt-2, I-tt-3, It t-4, I-tt-5, I-tt-6, I-tt-7 or I-tt-8: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, L, x, y and [ka] Each of these is as described and defined in WO2017 / 161119. Each is incorporated herein by reference in its entirety.

[0258] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). is a linking moiety, whereby the compound of formula I-uu: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. wherein each of the variables A, B, C, W, X, Y and Z is as described in US 5,721,246 and as defined herein, each of which is incorporated by reference in its entirety. can be.

[0259] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the compound of formula I-vv: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. and each of the variables R1, R2 and n is as defined and set forth in WO2019 / 043214. and the entirety of each of which is incorporated herein by reference.

[0260] In some embodiments, the LBM is prepared as described in Varfolomeev, E. et al. l., IAP Antagonists Induce Autoubiquitin ation of c-IAPs, NF-κB activation, and T NFα-Dependent Apoptosis, Cell, 2007, 131 (4): 669-81. For example: [ka] etc., where [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0261] In a specific embodiment, the present invention provides a method for the preparation of a VHL E3 ubiquitin ligase binding site (LBM). minutes, whereby the formulas I-ww-1, I-ww-2, I-ww-3, and I -WWIV or WWV: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable R 1’ , R 2’ , R 3’ , X and X' are each a group defined in WO2013 / 1066 43 and US2014 / 0356322, each of which is incorporated herein by reference in its entirety.

[0262] In a specific embodiment, the present invention provides a method for the preparation of a VHL E3 ubiquitin ligase binding site (LBM). minutes, whereby the formulae I-xx-1, I-xx-2, I-xx-3, and I -xx-4, I-xx-5 or I-xx-6: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable R 1’ , R 2’ , R 3’ , R5, R6, R7, R9, R 10 , R 11 , R1 4. R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X', Y, Z1, Z2 , Z3, Z4 and o are each defined in WO2016 / 149668 and US2016 / 02 72639, each of which is incorporated herein in its entirety. Incorporated by reference.

[0263] As used herein, the illustration of brackets surrounding any LBM [ka] teeth, [ka] The moiety is attached to the LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For clarity and as an example, the following LBM compound is Such available modifiable carbon, nitrogen, oxygen or sulfur atoms in the product structure are where each wavy line bond is [ka] Defines a connection point to

[0264] In a specific embodiment, the present invention provides a method for the preparation of a VHL E3 ubiquitin ligase binding site (LBM). minutes, whereby the formula I-yy-1, I-yy-2 or I-yy-3 : [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable R p , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 and o are each described in WO2016 / 118666 and US2 016 / 0214972, each of which in its entirety is as defined and described in It is incorporated herein by reference.

[0265] In certain embodiments, the present invention relates to a method for producing a CRBN or VHL E3 ubiquitin LBM. ligase binding moieties, thereby having the formulas I-zz-1, I-zz-2, and I-zz-3, respectively. -zz-3, I-zz-4, I-zz-5, I-zz-6, or I-zz-7: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable A 1 , A 2 , A 3 , R 5 , G and Z are each As defined and described in § 8.

[0266] In certain embodiments, the present invention provides a method for the production of CRBN E3 ubiquitin ligase-binding LBMs. moieties of the formula I-zz'-1, I-zz"-1, I-zz', -2, I-zz'-2, I-zz'-3, I-zz"-3, I-zz'-4, I-zz" -4, I-zz'-7 or I-zz”-7: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable A 1 , A 2 , A 3 , R5 , G and Z are each 8, the entire contents of which are incorporated herein by reference. do.

[0267] In certain embodiments, the present invention relates to a method for producing LBM comprising the steps of: or HDM2) E3 ligase binding moieties, whereby 1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa- 6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa -11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, or I-aaa-18: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R 6’ , R 7’ , R 8’ , R 9’ , R 10’ , R 11’ , R 12’ , R 1” , A, A', A", X, Y and Z are each defined in WO2017 / 011371 and As defined and described in US2017 / 0008904, and each of these The bodies are incorporated herein by reference.

[0268] In certain embodiments, the present invention provides a method for identifying an IAP E3 ubiquitin ligase binding site. minutes, whereby the formulas I-bbb-1, I-bbb-2, and I-bbb- 3 or I-bbb-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. Yes, variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each of the above is a WO2017 / As defined and described in US 2017 / 0037004 and US 2017 / 0037004. , each of which is incorporated herein by reference in its entirety.

[0269] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). binding moiety, DCAF15 E3 ubiquitin ligase binding moiety or VHL E3 ubiquitin a ligase binding moiety, whereby the moiety has the formula I-ccc-1, I-ccc-2 or I- -ccc-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and as described in embodiments herein. can be, X 1 , X 2a and X 3a each independently represents a covalent bond, —CH—, —C(O)—, — C(S)-, or [ka] is a divalent moiety selected from: X 4a and X 5a each independently represents -CH2-, -C(O)-, -C(S)-, or teeth [ka] is a divalent moiety selected from: R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, - S(O)R, -NR, or optionally substituted C 1~4 It is aliphatic; R 2 , R 3b and R 4aeach independently represents hydrogen, -R 6 , halogen, -CN, -NO 2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC( O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N( -R)C(O)NR2, or -N(R)S(O)2R; R 5a is hydrogen or C 1~6 is aliphatic, Each R 6 independently, C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms. and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from 5- to 6-membered heteroaryl rings; Ring A a is a 6-membered aryl, 5-membered to 7-membered partially saturated carbocyclic alkyl group containing 0 to 2 nitrogen atoms. cyclyl, having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 5- to 7-membered partially saturated heterocyclyl, fused 5-membered heteroaryl having 1 to 3 heteroatoms selected from It is a ring; Ring B a is a 6-membered aryl containing 0 to 2 nitrogen atoms, or nitrogen, oxygen, or sulfur an 8- to 10-membered bicyclic heterocyclic ring having 1 to 5 heteroatoms independently selected from Selected from the reels; Ring C a is a 6-membered aryl containing 0 to 2 nitrogen atoms, or nitrogen, oxygen, or sulfur and a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from be; m is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, The group is C 1~6 independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur 4- to 7-membered saturated or partially unsaturated heterocyclic rings containing 1 to 2 heteroatoms, and 5-membered alkyl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur a 6-membered heteroaryl ring; or Two R groups on the same nitrogen, together with the atoms between them as needed, form a and 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; It forms a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0270] In a specific embodiment, the present invention relates to a method for treating LBM-mediated ubiquitination in mammals, comprising administering to mammals the LBM an E3 ubiquitin ligase (cereblon). a linking moiety, whereby the compound has the formula I-ccc'-1 or I-ccc"-1: [ka] or a pharmaceutically acceptable salt thereof, where IRAK, L, and A are a , X 1 , X 2a , X 3a , R 1 , R 2 and m is , as mentioned above.

[0271] X, as defined above and described herein 1 , X 2a and X 3a Each of independently a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from

[0272] In some embodiments, X 1 is a covalent bond, -CH2-, -C(O)-, -C( S)-, or [ka] is.

[0273] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0274] In some embodime...

Claims

**Claim 1** A compound of formula I”-a: 【Chemical 2443】 or a pharmaceutically acceptable salt thereof, wherein in formula I”-a: each Rx is independently hydrogen, Rz, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N+(O-)R2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -P(O)R2, -SiR3, -Si(OR)R2, or 【Chemical 2444】 or; alternatively two Rx groups together form an optionally substituted 5- to 6-membered partially unsaturated ring or aryl fused ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic spiro fused ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, each R is independently hydrogen or an optionally substituted group, said optionally substituted group being selected from C1-6 aliphatic, phenyl, and 3- to 7-membered saturated or partially unsaturated heterocyclic having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same atom together with the atom between them form a 4- to 11-membered saturated or partially unsaturated carbocyclic ring, or a heterocyclic monocyclic, bicyclic, bridged bicyclic, spiro or heteroaryl ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the atoms to which they are attached; Each Ry is independently hydrogen, Rz, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -CFR₂, -CF₂R, -CF₃, -CR₂(OR), -CR₂(NR₂), -C(O)R, -C(O)OR, -C(O)NR₂, -C(S)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)S(O)₂R, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)NR₂, -OP(O)(NR₂)₂, -SiR₃, -SF₅, or 【Chemical 2445】 is; or a single Ry and a single Rx, together with the atoms therebetween, form a monocyclic or bicyclic heterocyclic ring having 8 to 20 members, saturated or partially unsaturated, and having 1 to 10 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a carbocyclic ring; each Rz is independently a C₁₋₆ aliphatic, phenyl, a monocyclic, bicyclic, bridged bicyclic, or spirocyclic ring having 4 to 9 members, saturated or partially unsaturated, and having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a heterocyclic ring, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted group as selected, if necessary; ring P and ring Q are independently selected from benzo, a 4- to 7-membered, saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused ring selected from a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ring T is selected from phenyl, a 4- to 7-membered, saturated or partially unsaturated carbocyclic 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; Lx is a covalent bond or a C1-3 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of said chain are independently replaced, as required, by -Cyx-, -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, -N=CR-, -CR=CR- or -S(O)2-, where R in -CR2-, -CRF-, -NR-, -N=CR- or -CR=CR- can combine with Rx or Ry to form a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having one to three heteroatoms independently selected from nitrogen, oxygen and sulfur; -Cyx- is an optionally substituted ring selected from a 3- to 5-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having zero to three heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-membered heteroaryl ring having one to four heteroatoms independently selected from nitrogen, oxygen and sulfur; X is a covalent bond or a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur; 【Chemical 2446】 is a single bond or a double bond; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or unsaturated straight-chain or branched C1-50 hydrocarbon chain, where zero to six methylene units of L are independently replaced by -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-, 【Chemical 2447】 being replaced thereby, where Each -Cy- is independently a divalent ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclirenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclirenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclirenyl, 4- to 7-membered saturated or partially unsaturated heterocyclirenyl having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur, 4- to 11-membered saturated or partially unsaturated spiroheterocyclirenyl having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclirenyl having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 6-membered heteroarylenyl having one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having one to five heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; DIM is a ligase binding moiety (LBM), and the LBM is (i) Formula I-aa: 【Chemical 2448】 or a cereblon E3 ubiquitin ligase binding moiety of a pharmaceutically acceptable salt thereof, where X1 is a divalent moiety selected from a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or 【Chemical 2449】 ; X2 is a carbon atom or a silicon atom; X3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S- or -Si(R2)-; R1 is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or a C1-4 aliphatic optionally substituted; Each R₂ is independently hydrogen, -R₆, halogen, -CN, -NO₂, -OR, -SR, -N(R)₂, -Si(R)₃, -S(O)₂R, -S(O)₂N(R)₂, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)₂, -C(O)N(R)OR, -C(R)₂N(R)C(O)R, -C(R)₂N(R)C(O)N(R)₂, -OC(O)R, -OC(O)N(R)₂, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)(NR₂), -OP(O)(NR₂)₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)₂, -N(R)S(O)₂R, -NP(O)R₂, -N(R)P(O)(OR)₂, -N(R)P(O)(OR)(NR₂), -N(R)P(O)(NR₂)₂, or -N(R)S(O)₂R; Ring A is 【Chemical 2450】 【Chemical 2451】 【Chemical 2452】 a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R₃ is selected from hydrogen, halogen, -OR, -N(R)₂, or -SR; Each R₄ is independently hydrogen, -R₆, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂ or -N(R)S(O)₂R; R₅ is hydrogen, C₁₋₄ aliphatic, or -CN; Each R6 is independently a group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from C1-6 aliphatic, phenyl, nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted; L1 is a covalent bond, or a C1-3 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2- or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen, or an optionally substituted group, and the optionally substituted group is selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from C1-6 aliphatic, phenyl, nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: Two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated ring, partially unsaturated ring, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to said nitrogen; or (ii) 【Chemical 2453】 【Chemical 2454】 A compound or a pharmaceutically acceptable salt thereof. **Claim 2**: The compound according to claim 1, wherein the compound is any one of the following formulas: 【Chemical 2455】 【Chemical 2456】 【Chemical 2457】 【Chemical 2458】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is any one of the following formulas: **Claim 3**: The compound according to claim 1 or claim 2, wherein the compound is any one of the following formulas: 【Chemical 2459】 【Chemical 2460】 【Chemical 2461】 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, which is any one of the following formulas: **Claim 4**: Rx is fluoro, -Me, -CF2H, -OMe, -OEt, -OiPr, -OCF2H, -OCF3, -SMe, -S(O)2Me, 【Chemical 2462】 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3. **Claim 5** The cyclic group T is phenyl or a 5- to 9-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. **Claim 6** The cyclic group T is phenyl, 【Chemical 2463】 the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. **Claim 7** Ry is fluoro, chloro, -CN, -CF₂Me, -CFMe₂, -CF₃, -Me, -OCF₃, cyclopropyl, 【Chemical 2464】 the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. **Claim 8** X is 【Chemical 2465】 the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. **Claim 9** The cyclic group A is 【Chemical Formula 2466】 the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof. **Claim 10** LBM is 【Chemical 2467】 the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 2468】 is 【Chemical 2469】 【Chemical 2470】 【Chemical 2471】 【Chemical 2472】 【Chemical 2473】 【Chemical 2474】 【Chemical 2475】 【Chemical 2476】 【Chemical 2477】 【Chemical 2478】 【Chemical 2479】 【Chemical 2480】 【Chemical 2481】 【Chemical 2482】 【Chemical 2483】 【Chemical 2484】 the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. **Claim 12** L is a divalent saturated or unsaturated straight-chain or branched-chain C₁₋₃₀ hydrocarbon chain, where 0 to 6 methylene units of L are independently replaced by -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)-, or -N(R)C(O)O-, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. **Claim 13** -Cy- is 【Chemical 2485】 the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. **Claim 14** L is 【Chemical 2486】 【Chemical 2487】 【Chemical 2488】 【Chemical 2489】 【Chemical 2490】 【Chemical 2491】 【Chemical 2492】 【Chemical 2493】 【Chemical 2494】 【Chemical 2495】 【Chemical 2496】 【Chemical 2497】 【Chemical 2498】 【Chemical 2499】 【Chemical 2500】 【Chemical 2501】 【Chemical 2502】 【Chemical 2503】 【Chemical 2504】 【Chemical 2505】 【Chemical 2506】 【Chemical 2507】 【Chemical 2508】 【Chemical 2509】 【Chemical 2510】 【Chemical 2511】 the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. **Claim 15** The compound is selected from any one of the following compounds: 【Chemical 2512】 【Chemical 2513】 【Chemical 2514】 【Chemical 2515】 【Chemical 2516】 【Chemical 2517】 【Chemical 2518】 【Chemical 2519】 【Chemical 2520】 【Chemical 2521】 【Chemical 2522】 【Chemical 2523】 【Chemical 2524】 【Chemical 2525】 【Chemical 2526】 【Chemical 2527】 【Chemical 2528】 【Chemical 2529】 【Chemical 2530】 【Chemical 2531】 【Chemical 2532】 【Chemical 2533】 【Chemical 2534】 【Chemical 2535】 【Chemical 2536】 【Chemical 2537】 【Chemical 2538】 【Chemical 2539】 【Chemical 2540】 【Chemical 2541】 【Chemical 2542】 【Chemical 2543】 【Chemical 2544】 【Chemical 2545】 【Chemical 2546】 【Chemical 2547】 【Chemical 2548】 【Chemical 2549】 【Chemical 2550】 【Chemical 2551】 【Chemical 2552】 【Chemical 2553】 【Chemical 2554】 【Chemical 2555】 【Chemical 2556】 【Chemical 2557】 【Chemical 2558】 【Chemical 2559】 【Chemical 2560】 【Chemical 2561】 【Chemical 2562】 【Chemical 2563】 【Chemical 2564】 【Chemical 2565】 【Chemical 2566】 【Chemical 2567】 【Chemical 2568】 【Chemical 2569】 【Chemical 2570】 【Chemical 2571】 the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17. A composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of degrading and / or inhibiting IRAK4 in a patient or a biological sample, the method comprising administering the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition to the patient or contacting the biological sample therewith.

18. A composition for treating a disorder, disease, or condition mediated by IRAK4 in a patient, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

19. The disorder, disease, or condition mediated by IRAK4 is selected from the group consisting of cancer, neurodegenerative disorder, viral disease, autoimmune disease, inflammatory disorder, genetic disorder, hormone-related disease, metabolic disorder, condition related to organ transplantation, immunodeficiency disorder, destructive bone disorder, proliferative disorder, infectious disease, condition related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immune state involving T cell activation, cardiovascular disorder, and CNS disorder. The composition according to claim 18. **Claim 20**: The cancer or proliferative disorder is a benign or malignant tumor, solid tumor, carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, colon cancer, colorectal adenoma, head and neck tumor, epidermal hyperplasia, psoriasis, prostatic hypertrophy, neoplasm, neoplasm with epithelial characteristics, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin or non-Hodgkin lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorder, MyD88-driven disorder, smoldering or asymptomatic multiple myeloma, and leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma, selected from the group consisting of hematological malignancies, the composition according to claim 19. **Claim 21**: The MyD88-driven disorder is selected from the group consisting of ABC DLBCL, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia, the composition according to claim 20.

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