STAT degraders and uses thereof

Abstract

To provide STAT degraders and uses thereof.SOLUTION: The present invention provides compounds, compositions thereof, and methods of using the compositions. In some embodiments, the present invention provides a method of treating a hematologic malignancy selected from LGL leukemia (T cell and NK cell), cutaneous T cell lymphoma (CTCL), peripheral T cell lymphomas (PTCL, all subtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acute myelogenous leukemia, multiple myeloma, and myelofibrosis.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This application is a joint venture between U.S. Provisional Application No. 62 / 830,095 (filed April 5, 2019), U.S. Provisional Application No. 62 / 833,331 (filed April 12, 2019), U.S. Provisional Application No. 62 / 855,259 (filed May 31, 2019), U.S. Provisional Application No. 62 / 860,512 (filed June 12, 2019), U.S. Provisional Application No. 62 / 875,362 (filed July 17, 2019), U.S. Provisional Application No. 62 / 877,051 (filed July 22, 2019), U.S. Provisional Application No. 62 / 887,872 (filed August 16, 2019), and U.S. Provisional Application No. 62 / 887,872. This application claims the benefit of U.S. Provisional Application No. 62 / 926,127, filed October 25, 2019, U.S. Provisional Application No. 62 / 932,957, filed November 8, 2019, U.S. Provisional Application No. 62 / 944,810, filed December 6, 2019, U.S. Provisional Application No. 62 / 947,310, filed December 12, 2019, U.S. Provisional Application No. 62 / 949,053, filed December 17, 2019, and U.S. Provisional Application No. 62 / 967,921, filed January 30, 2020, the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of one or more signal transducers and activators of transcription ("STATs") by ubiquitination and / or degradation by compounds according to the invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

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

[0004] There are over 600 E3 ubiquitin ligases that facilitate the ubiquitination of various proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. Generally, Li et al. (PLOS One, 2008, 3, 1487) titled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling." Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled "New insights into ubiquitin E3 ligase mechanism." Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled "RING domain E3 ubiquitin ligases.”;Spratt et al. (Biochem. 2014, 458, 421-437) entitled "RBR E3 ubiquitin ligases: new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled "Roles of F-box proteins in cancer."

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

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

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents and provide a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). There is a continuing need in the art for effective treatment of diseases, particularly hyperplasia and cancer, such as breast cancer.However, non-specific effects and the inability to target and regulate specific classes of proteins (e.g., transcription factors) together remain obstacles to the development of effective anti-cancer drugs.Therefore, small molecule therapeutic agents that affect E3 ligase-mediated protein degradation and target cancer-related proteins, such as signal transducers and activators of transcription ("STATs"), hold promise as therapeutic agents.Therefore, there remains a need to find compounds that are STAT 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 relates to novel bifunctional compounds that function to recruit STAT proteins to E3 ubiquitin ligases for degradation, as well as methods for their preparation and use. In particular, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of STAT proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. Monovalent compounds that find utility as inducers of targeted ubiquitination of STAT proteins, which are then degraded and / or otherwise inhibited by the monovalent compounds described herein, are also provided. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, consistent with the degradation / inhibition of STAT proteins. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein to treat or alleviate disease conditions, such as cancer, e.g., breast cancer.

[0010] The present application further relates to the targeted degradation of STAT proteins through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds to the targeted STAT protein.

[0011] It has now been found that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of STAT proteins. Such compounds have the general formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] It has also now been found that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of STAT proteins. Such compounds have the general formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0014] The compounds provided by the present invention are also useful for the study of STAT enzymes in biological and pathological phenomena; for the study of intracellular signaling pathways occurring in body tissues; and for the comparative evaluation of novel STAT inhibitors or STAT degraders, or other regulators of the cell cycle, metastasis, angiogenesis, and immune cell evasion in vitro or in vivo. 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: STAT is a STAT protein binding moiety capable of binding to one or more of STAT3, STAT1, STAT2, STAT4, STAT5A, STAT5B, and STAT6; L is a bivalent moiety that binds STAT to LBM; and LBM is the E3 ubiquitin ligase binding moiety. The compound or a pharmaceutically acceptable salt thereof. (Item 2) 2. The compound of item 1, wherein the LBM is a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. (Item 3) The LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ic: X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R 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; Ring A is [ka] [ka] 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 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; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 2. (Item 4) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has the formula If: [ka] or a pharmaceutically acceptable salt thereof, wherein: 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] 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 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; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 2. (Item 5) The LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has formula Ih: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ih: 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] 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 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; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound according to item 2. (Item 6) LBM is a cereblon E3 ubiquitin ligase binding moiety, and the compound has formula Ij: [ka] or a pharmaceutically acceptable salt thereof, in formula Ij: X 1is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -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 is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of 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 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; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; The compound according to item 2. (Item 7) LBM is the cereblon E3 ubiquitin ligase binding moiety, and the compound has the following formula: (i) [ka] or a pharmaceutically acceptable salt thereof, [ka] , X, X1, X2, Y, R1, R3, R3', R4, R5, t, m, and n are as defined and described in WO 2017 / 007612 and US 2018 / 0134684, each of which is incorporated by reference in its entirety; (ii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables A, G, G', Q1, Q2, Q3, Q4, R, R', W, X, Y, Z, [ka] each of n is as defined and described in WO 2016 / 197114 and US 2018 / 0147202, each of which is incorporated by reference in its entirety; (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 WO 2017 / 176958, the entirety of each of which is incorporated herein by reference; (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] each as described and defined in WO 2017 / 161119, the entirety of each of which is incorporated herein by reference; (v) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 ,X, [ka] each of n is as defined in WO 2018 / 237026, 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 The binding site of [ka] But R 12 occupying a substituent position; or (vi) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 ,X, [ka] each of n is as defined in WO 2017 / 197051, the entirety of each of which is incorporated herein by reference; and [ka] is R as defined in WO 2017 / 197051 1 , R 1 and R 2 or R 17 To, R 12 The binding site of [ka] But R 12 Occupying the position of a substituent Item 1. The compound according to item 1, selected from any one of (Item 8) The cereblon E3 ubiquitin ligase binding portion: [ka] [ka] 3. The compound according to item 2, selected from the group consisting of: (Item 9) LBM is a VHL E3 ubiquitin ligase binding moiety, and the compound has the following formula: (i) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1’ , R 2’ , R 3’ , X, and X′ are each as defined and described in WO 2013 / 106643 and US 2014 / 0356322, each of which is incorporated by reference in its entirety; (ii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1’ , R 2’ , R 3’ , R5, R6, R7, R9, R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X', Y, Z1, Z2, Z3, Z4, and o are as defined and described in WO 2016 / 149668 and US 2016 / 0272639, each of which is incorporated by reference in its entirety; or (iii) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R p , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 each of o and o is as defined and described in WO 2016 / 118666 and US 2016 / 0214972, each of which is incorporated by reference in its entirety; Item 3. The compound according to item 2, selected from any one of (Item 10) The VHL E3 ubiquitin ligase binding moiety is: [ka] [ka] Item 3. The compound according to item 2, selected from: (Item 11) 3. The compound according to item 2, wherein STAT is a STAT protein binding moiety capable of binding to STAT3. (Item 12) The compound has the following formula: (i) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, R5, and R6 is as described and defined in US 2004 / 0138189, the entirety of each of which is incorporated herein by reference; (ii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R0, R2, R3, and R4 are as described and defined in US 2005 / 0277680, each of which is incorporated herein by reference in its entirety; (iii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R6, AA, and n are as described and defined in US 2008 / 0139456, the entirety of each of which is incorporated herein by reference; (iv) [ka] or a pharmaceutically acceptable salt thereof, in which one or more amino acids are replaced with a structural analogue as described and defined in US 2007 / 0010428, each of which is incorporated herein by reference in its entirety; (v) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables A, B, Z, n, and m is as described and defined in WO 2007 / 042912 and US 7,786,142, each of which is incorporated by reference in its entirety; (vi) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, X, and Z are as described and defined in US 7,960,434, the entirety of each of which is incorporated herein by reference; (vii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 each of A, X1, and Y is as described and defined in US 8,263,599, the entirety of each of which is incorporated herein by reference; (viii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 1’ , R 2 , R 3 , R 6 each of , AA, and n is as described and defined in WO 2008 / 067270, the entirety of each of which is incorporated herein by reference; (ix) [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables R, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 each of x, x, and y is as described and defined in WO 2008 / 156644 and US 2011 / 0144043, each of which is incorporated by reference in its entirety; (x) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7each of W, W, and X is as described and defined in WO 2010 / 004761 and US 8,446,290, each of which is incorporated by reference in its entirety; (xi) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables Ro, R2, R3, R4, and n is as described and defined in WO 2010 / 005807 and US 8,143,412, each of which is incorporated by reference in its entirety; (xii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 , R 4 , X, and Y are as described and defined in WO 2010 / 077589 and US 2011 / 0319362, each of which is incorporated by reference in its entirety; (xiii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 each of Z, X, and Y is as described and defined in WO 2010 / 118309 and US 8,841,257, the entireties of which are incorporated herein by reference; (xiv) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , A, Z, X, Y, a, and b are as described and defined in WO 2010 / 121007 and US 2012 / 0053208, each of which is incorporated by reference in its entirety; (xv) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, R5, R6, R7, R8, and R9 is as described and defined in WO 2011 / 066263, WO 2012 / 097351, and US 8,883,749, each of which is incorporated by reference in its entirety; (xvi) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R, Ar, X, and Y are as described and defined in WO 2011 / 081205 and US 2012 / 302524, each of which is incorporated by reference in its entirety; (xvii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, and R4 is as described and defined in WO 2011 / 163424 and US 2013 / 0172340, each of which is incorporated by reference in its entirety; (xviii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, and R4 is as described and defined in WO 2012 / 018868 and US 2013 / 0225621, each of which is incorporated by reference in its entirety; (xix) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, and X are as described and defined in WO 2012 / 078982, the entirety of each of which is incorporated herein by reference; (xx) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, and R5 is as described and defined in WO 2012 / 142615, the entirety of each of which is incorporated herein by reference; (xxi) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, m, and n is as described and defined in WO 2012 / 078982 and US 2015 / 0158894, each of which is incorporated by reference in its entirety; (xxii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R3, R4, Y, and [ka] each as described and defined in WO 2013 / 187965 and US 2015 / 0166484, each of which is incorporated by reference in its entirety; (xxiii) [ka] or a pharmaceutically acceptable salt thereof, wherein variable Q 1 , Q 2 , Q 3 , and R 1 each as described and defined in WO 2014 / 028909 and US 2015 / 0232434, each of which is incorporated by reference in its entirety; (xxiv) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 , R 6 each of Z, Z, and Y is as described and defined in WO 2014 / 070859 and US 2015 / 0259366, each of which is incorporated by reference in its entirety; (xxv) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, X1, X2, X3, X4, and X5 is as described and defined in WO 2014 / 153495 and US 2016 / 0068478, each of which is incorporated by reference in its entirety; (xxvi) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, and R3 is as described and defined in WO 2014 / 205416 and US 2016 / 0137663, each of which is incorporated by reference in its entirety; (xxvii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R is as described and defined in US 2016 / 0060239, each of which is incorporated herein by reference in its entirety; (xxviii) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables ring A, ring B, X1, X2, X3, X4, Y, Z, R A , R B , R C , R N , R X , L B , p, q, and [ka] each as described and defined in WO 2016 / 089060 and US 2017 / 0320889, each of which is incorporated by reference herein in its entirety; (xxix) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1 and R2 is as described and defined in WO 2016 / 115455, the entirety of each of which is incorporated herein by reference; (xxx) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 each as described and defined in WO 2016 / 125169 and US 2018 / 0028475, each of which is incorporated by reference in its entirety; (xxxi) [ka] or a pharmaceutically acceptable salt thereof, wherein the variable 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 13 , R 14 each as described and defined in WO 2016 / 193332 and US 2018 / 0155360, each of which is incorporated by reference in its entirety; (xxxii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R2', R3, R3', R4, R4', R5, R6, A, X, Cy1, and m are as described and defined in WO 2018 / 104295, the entirety of each of which is incorporated herein by reference; or (xxxiii) [ka] or a pharmaceutically acceptable salt thereof, wherein each of the variables R1, R2, R3, R4, R5, R6, R7, R8, Q, W, t, p, and y are as described and defined in WO 2018 / 136935, each of which is incorporated by reference in its entirety; Item 12. The compound according to item 11, selected from any one of: (Item 13) The STAT3 binding moiety is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Item 12. The compound according to item 11, selected from: (Item 14) L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50a 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] 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, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, a saturated or partially unsaturated heterocyclylenyl of an 8- to 10-membered bicyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The compound according to any one of items 1 to 13. (Item 15) L is a covalent bond, [ka] [ka] [ka] [ka] [ka] [ka] Item 15. The compound according to item 14, selected from: (Item 16) 16. The compound according to any one of items 1 to 15, wherein the compound is selected from any one of the compounds depicted in Table 1 or a pharmaceutically acceptable salt thereof. (Item 17) A pharmaceutical composition comprising the compound according to item 16 and a pharmaceutically acceptable carrier, adjuvant, or vehicle. (Item 18) 18. The pharmaceutical composition of item 17, further comprising an additional therapeutic agent. (Item 19) A method for degrading STAT3 protein in a patient or a biological sample, comprising administering to the patient or contacting with the biological sample a compound according to any one of items 1 to 16, or a pharmaceutical composition thereof. (Item 20) 17. A method of treating a STAT3-mediated disorder, disease, or condition in a patient, comprising administering to the patient a compound according to any one of items 1 to 16, or a pharmaceutical composition thereof. (Item 21) 21. The method of claim 20, further comprising administering an additional therapeutic agent. (Item 22) 21. The method of claim 20, wherein the STAT3-mediated disorder, disease or condition is selected from cancer, a neurodegenerative disease, a viral 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. (Item 23) 23. The method of claim 22, wherein the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma, ovarian cancer, malignant peripheral nerve sheath tumor (MPNST), pancreatic cancer, non-small cell lung cancer, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, and hematological malignancies. (Item 24) 23. The method of item 22, wherein the autoimmune disease is selected from systemic sclerosis, idiopathic pulmonary fibrosis, inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, acute graft-versus-host disease, chronic graft-versus-host disease, and tissue fibrosis diseases. (Item 25) 24. The method of item 23, wherein the hematological malignancy is selected from large granular lymphocytic (LGL) leukemia (T-cell and NK-cell), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia, multiple myeloma, and myelofibrosis. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the binding IC50 (μM) of I-1 to both STAT3 and E3 ligase.

[0016] [Figure 2] Figure 2 contains images of the results of AlphaLISA assays of I-1 (A) and A549 lysates (B), demonstrating efficient ternary complex formation and STAT3 ubiquitination.

[0017] [Figure 3] FIG. 3 includes graphical images showing the results of an endogenous STAT3-HiBiT viable cell assay in A549 (A) using HiBiT signal (% control) (y-axis) at 0.5, 1, 2, 4, 6, 8, 24, and 48 hours versus I-103 concentration (nM) (x-axis), and an MSD assay of STAT3 levels at 24 hours in heme cell lines MOLM-16 and SU-DHL-1 (B) using STAT3 protein (% control) (y-axis) versus I-103 concentration (nM) (x-axis).

[0018] [Figure 4-1] Figure 4 contains images of deep tandem mass tag (TMT) proteomic scatter plots at 8 hours in MOLM-16 (AML) and SU-DHL-1 (ALCL), showing the -Log10 p-value (y-axis) and Log2 fold change (x-axis) of I-103 at 30 nM and 100 nM in DMSO. [Figure 4-2] Figure 4 contains images of deep tandem mass tag (TMT) proteomic scatter plots at 8 hours in MOLM-16 (AML) and SU-DHL-1 (ALCL), showing the -Log10 p-value (y-axis) and Log2 fold change (x-axis) of I-103 at 30 nM and 100 nM in DMSO.

[0019] [Figure 5] Figure 5 shows graphical images and tables depicting (A) RT-qPCR results for SU-DHL-1 cells at 24 hours using mRNA levels (% control) versus I-103 concentration (nM) (x-axis) for the STAT3, SOCS3, and PDL-1 genes, and (B) CellTiterGlo (CTG) cell viability results for MOLM-16 and SU-DHL-1 cell lines at 4 days using growth inhibition (% control) versus I-103 concentration (nM) (x-axis). Also shown are MSD degradation DC50 (nM) results for MOLM-16 and SU-DHL-1 cell lines at 24 hours.

[0020] [Figure 6-1] Figure 6 shows STAT3 and pSTAT3 degradation (A), median tumor volume (mm) versus days (post-randomization) for vehicle, 25 mg / kg IP QD, and 50 and 100 mg / kg SC BIW dosing. Efficacy in NOD / SCID mice (B), STAT3 and pSTAT3 (relative STAT3 / actin) (left y-axis) and plasma concentrations (μM) (right y-axis) for vehicle, 25 mg / kg IP (2 days on / 5 days off), 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg Contains graphical images of MOLM-16 and SU-DHL-1 tumor xenograft results using I-103 for efficacy in NOD / SCID mice using median tumor volume (mm) versus days (post-randomization) for IP (2 days on / 5 days off) dosing (D), and observed body weight change in NOD / SCID mice for vehicle, 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg IP (2 days on / 5 days off) dosing (E). [Figure 6-2]Figure 6 shows STAT3 and pSTAT3 degradation (A), median tumor volume (mm) versus days (post-randomization) for vehicle, 25 mg / kg IP QD, and 50 and 100 mg / kg SC BIW dosing. Efficacy in NOD / SCID mice (B), STAT3 and pSTAT3 (relative STAT3 / actin) (left y-axis) and plasma concentrations (μM) (right y-axis) for vehicle, 25 mg / kg IP (2 days on / 5 days off), 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg Contains graphical images of MOLM-16 and SU-DHL-1 tumor xenograft results using I-103 for efficacy in NOD / SCID mice using median tumor volume (mm) versus days (post-randomization) for IP (2 days on / 5 days off) dosing (D), and observed body weight change in NOD / SCID mice for vehicle, 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg IP (2 days on / 5 days off) dosing (E). [Figure 6-3]Figure 6 shows STAT3 and pSTAT3 degradation (A), median tumor volume (mm) versus days (post-randomization) for vehicle, 25 mg / kg IP QD, and 50 and 100 mg / kg SC BIW dosing. Efficacy in NOD / SCID mice (B), STAT3 and pSTAT3 (relative STAT3 / actin) (left y-axis) and plasma concentrations (μM) (right y-axis) for vehicle, 25 mg / kg IP (2 days on / 5 days off), 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg Contains graphical images of MOLM-16 and SU-DHL-1 tumor xenograft results using I-103 for efficacy in NOD / SCID mice using median tumor volume (mm) versus days (post-randomization) for IP (2 days on / 5 days off) dosing (D), and observed body weight change in NOD / SCID mice for vehicle, 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg IP (2 days on / 5 days off) dosing (E). [Figure 6-4]Figure 6 shows STAT3 and pSTAT3 degradation (A), median tumor volume (mm) versus days (post-randomization) for vehicle, 25 mg / kg IP QD, and 50 and 100 mg / kg SC BIW dosing. Efficacy in NOD / SCID mice (B), STAT3 and pSTAT3 (relative STAT3 / actin) (left y-axis) and plasma concentrations (μM) (right y-axis) for vehicle, 25 mg / kg IP (2 days on / 5 days off), 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg Contains graphical images of MOLM-16 and SU-DHL-1 tumor xenograft results using I-103 for efficacy in NOD / SCID mice using median tumor volume (mm) versus days (post-randomization) for IP (2 days on / 5 days off) dosing (D), and observed body weight change in NOD / SCID mice for vehicle, 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg IP (2 days on / 5 days off) dosing (E). [Figure 6-5]Figure 6 shows STAT3 and pSTAT3 degradation (A), median tumor volume (mm) versus days (post-randomization) for vehicle, 25 mg / kg IP QD, and 50 and 100 mg / kg SC BIW dosing. Efficacy in NOD / SCID mice (B), STAT3 and pSTAT3 (relative STAT3 / actin) (left y-axis) and plasma concentrations (μM) (right y-axis) for vehicle, 25 mg / kg IP (2 days on / 5 days off), 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg Contains graphical images of MOLM-16 and SU-DHL-1 tumor xenograft results using I-103 for efficacy in NOD / SCID mice using median tumor volume (mm) versus days (post-randomization) for IP (2 days on / 5 days off) dosing (D), and observed body weight change in NOD / SCID mice for vehicle, 50 mg / kg IP QW, 50 mg / kg IP Q2D, and 50 mg / kg IP (2 days on / 5 days off) dosing (E).

[0021] [Figure 7-1] Figure 7 illustrates the decrease in STAT3 observed at 24 hours of treatment with I-103 (A), the time-dependent growth inhibition with I-103 (B), the increase in activated caspase 3 at 48 hours leading to cell death with I-103 treatment (C), and the increase in subG1 cells observed with I-103 treatment (D). [Figure 7-2] Figure 7 illustrates the decrease in STAT3 observed at 24 hours of treatment with I-103 (A), the time-dependent growth inhibition with I-103 (B), the increase in activated caspase 3 at 48 hours leading to cell death with I-103 treatment (C), and the increase in subG1 cells observed with I-103 treatment (D). [Figure 7-3]Figure 7 illustrates the decrease in STAT3 observed at 24 hours of treatment with I-103 (A), the time-dependent growth inhibition with I-103 (B), the increase in activated caspase 3 at 48 hours leading to cell death with I-103 treatment (C), and the increase in subG1 cells observed with I-103 treatment (D).

[0022] [Figure 8] FIG. 8 illustrates that a 90% reduction of STAT3 using I-103 is required to induce SU-DHL-1 apoptosis and inhibit cell growth.

[0023] [Figure 9] FIG. 9 illustrates a dose-response curve showing that I-111 degrades mutant STAT3 (STAT D661Y) in the HDLM-2 cell line.

[0024] [Figure 10] FIG. 10 illustrates the results of a washout study using I-103 at 24 hours (A) and 48 hours (B).

[0025] [Figure 11] Figure 11 illustrates the decomposition of STAT3 reduction in STAT3 mutants using I-83 (3 μM, 24 h) in ectopically overexpressed HEK293 cells, showing Flag-STAT3 levels (% DMSO) (y-axis) for WT, D661Y(SH2), D661V(SH2), Y640F(SH2), and K392R(DBD) mutants (x-axis).

[0026] [Figure 12] FIG. 12 illustrates a dose-response curve showing that I-83 degrades mutant STAT3 (STAT D661Y) in the HDLM-2 cell line.

[0027] [Figure 13-1]Figure 13 contains images of deep tandem mass tag (TMT) proteomic scatter plots in SU-DHL-1 (ALCL) at 8 hours, showing the -Log10 p-value (y-axis) and Log2 fold change (x-axis) of I-174 at 150 nM, 350 nM, and 3.5 μM in DMSO. [Figure 13-2] Figure 13 contains images of deep tandem mass tag (TMT) proteomic scatter plots in SU-DHL-1 (ALCL) at 8 hours, showing the -Log10 p-value (y-axis) and Log2 fold change (x-axis) of I-174 at 150 nM, 350 nM, and 3.5 μM in DMSO.

[0028] [Figure 14] FIG. 14 illustrates dose-response curves and DC50 results showing that I-174 and I-94 mediated degradation in multiple ALK+ ALCL cell lines.

[0029] [Figure 15] FIG. 15 illustrates dose-response curves and IC50 results showing I-174 and I-94 inhibition of STAT3-mediated gene expression of SOCS3 and PD-L1 in SU-DHL-1 cells.

[0030] [Figure 16] FIG. 16 depicts dose-response curves showing that I-174 and I-94 mediated growth inhibition in multiple ALK+ ALCL cell lines.

[0031] [Figure 17] FIG. 17 illustrates that a 90% reduction of STAT3 using I-174 and I-94 is required to induce SU-DHL-1 apoptosis and inhibit cell growth.

[0032] [Figure 18]FIG. 18 illustrates the results of a washout study using I-174, showing strong growth inhibition and potential cell death after 4 days (24-hour washout), and complete growth inhibition and cell death after 4 days (48-hour washout) in SU-DHL-1 cells.

[0033] [Figure 19] FIG. 19 illustrates ALK+ALCL SU-DHL-1 mouse xenograft and KD results for STAT3 degradation using median tumor volume (mm) versus days (post-randomization) for vehicle, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, and 25 mg / kg (mpk) doses using I-174.

[0034] [Figure 20] Figure 20 contains ALK+ALCL SUP-M2 xenograft results for STAT3 degradation using I-174 with median tumor volume (mm) versus days (post-randomization) for vehicle, 3 mg / kg IV 2d on / 5d off, 10 mg / kg IV 2d on / 5d off, 30 mg / kg IV 2d on / 5d off, and 30 mg / kg IC QW dosing (top graph), and animal body weight (g) versus days (post-randomization) for FD 10 mg / kg 2d on / 5d off and 30 mg / kg 2d on / 5d off (bottom graph).

[0035] [Figure 21] FIG. 21 illustrates dose-response curves of the STAT3-HiBiT cell viability assay using I-174 and I-94 in A549 cells, with STAT3 protein (% control) (y-axis) versus compound concentration (nM) (x-axis) at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 48 hours. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of one or more STAT proteins. In some embodiments, provided compounds degrade and / or inhibit one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.

[0037] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6; L is a bivalent moiety that binds STAT to LBM; and LBM is the ligase binding moiety.

[0038] In certain embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II: STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6; L is a bivalent moiety that links STAT to DIM; and DIM is a degradation-inducing moiety.

[0039] 2. Compounds and definitions: The compounds of the present invention include those generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University of Science, the entire contents of which are incorporated herein by reference. Books, Sausalito: 1999, and in March's Advanced Organic Chemistry, 5th Edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0040] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring can be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring can contain one or more oxo (=O) or thioxo (=S) substituents. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0041] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0042] The term "lower alkyl" refers to C 1~4 " refers to a straight or branched chain alkyl group of the formula: Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0043] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0044] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0045] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0046] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0047] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0048] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0049] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] The term "cyclopropyl" refers to a divalent cyclopropyl group.

[0050] The term "halogen" means F, Cl, Br, or I.

[0051] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. As used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0052] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0053] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0054] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). In some embodiments, the heterocyclic ring can be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. The heterocyclic ring can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0055] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0056] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0057] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○which may be replaced by); -NO2; -CN; -N3; -(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 C(O)SR ○ ; -(CH2) 0~4 C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ ; -SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0058] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0059] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0064] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. In some embodiments, provided compounds are purified in salt form for convenience and / or ease of purification, for example, using acidic or basic mobile phases during chromatography. Salt forms of provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and will be readily apparent to those skilled in the art.

[0065] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0066] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0067] The term "prodrug" refers to a compound that is made more active in vivo. The compound is a compound that is made more active in vivo. As described in (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003), prodrugs may also exist. Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Furthermore, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug may be slowly converted to the compound when placed in a steroid patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, i.e., the parent drug. Prodrugs may be bioavailable, for example, by oral administration, while the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug, are known in the art. An example, without limitation, of a prodrug is a compound that is administered as an ester (the "prodrug"), but is then metabolically hydrolyzed to the carboxylic acid, the active entity. Further examples include peptidyl derivatives of compounds. The term "therapeutically acceptable prodrug" refers to a prodrug or zwitterion that is suitable for use in contact with patient tissues without undue toxicity, irritation, and allergic response, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0068] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits a STAT protein with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or have a binding constant.

[0069] As used herein, the term "degrading agent" is defined as a heterobifunctional compound that binds and / or inhibits both STAT proteins and E3 ligases with measurable affinity, resulting in ubiquitination and subsequent degradation of the STAT protein. In certain embodiments, a degrading agent has a DC activity of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 As used herein, the term "monovalent" refers to a degrader compound that does not have an E3 ligase binding moiety attached.

[0070] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0071] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P,35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0072] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0073] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0074] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0075] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in STAT protein activity between a sample containing a compound of the present invention or a composition thereof and STAT protein and an equivalent sample containing STAT protein without the compound or composition thereof present.

[0076] 3. Description of Exemplary Embodiments: As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: STAT is a STAT protein binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6; L is a bivalent moiety that binds STAT to LBM; and LBM is the E3 ubiquitin ligase binding moiety.

[0077] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: STAT is a STAT3 binding moiety; L is a bivalent moiety that binds STAT to LBM; and LBM is the cereblon E3 ubiquitin ligase binding moiety.

[0078] As noted above, in certain embodiments, the present invention provides compounds of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II: STAT is a STAT protein binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6; L is a bivalent moiety that links STAT to DIM; and DIM is a degradation-inducing moiety.

[0079] In some embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II: STAT is a STAT3 binding moiety; L is a bivalent moiety that links STAT to DIM; and DIM is an LBM, a lysine mimetic, or a hydrogen atom. Ligase binding moiety (LBM)

[0080] In some embodiments, the LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to those skilled in the art and are described in detail in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara. et al.Nature Chemical Biology 2017,13,675,WO 2017 / 176708, US 2017 / 0281784, WO 2017 / 161119, WO 2017 / 176957, WO 2017 / 176958, WO 2015 / 160845, US 2015 / 0291562, WO 2016 / 197032, WO 2016 / 105518, US 2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, WO 2017 / 197046, WO 2017 / 197051, WO 2017 / 197055, and WO 2017 / 197056, each of which is incorporated by reference in its entirety.

[0081] As defined herein and described below, formulas may be expressed using square brackets, e.g., [ka] where L is attached to a modifiable carbon, oxygen, or nitrogen atom in the DIM or LBM and includes the substitution or replacement of the defined group on the DIM or LBM.

[0082] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing Formula Ia-1, Ia-2, Ia-3, Ia-4, Ia-5, Ia-6, Ia-7, Ia-8, Ia-9, or Ia-10, respectively: [ka] or a pharmaceutically acceptable salt thereof, or a compound of formula I-a'-1, I-a'-2, I-a'-3, I-a'-4, I-a'-5, I-a'-6, I-a'-7, I-a'-8, I-a'-9, or I-a'-10, respectively: [ka] or a compound of formula I-a''-1, I-a''-2, I-a''-3, I-a''-4, I-a''-5, I-a''-6, I-a''-7, I-a''-8, I-a''-9, or I-a''-10, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and STAT are as defined above and as described in embodiments herein, and the variables [ka] , X, X1, X2, Y, R1, R3, R3', R4, R5, t, m, and n are as defined and described in WO 2017 / 007612 and US 2018 / 0134684, each of which is incorporated by reference in its entirety.

[0083] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing Formula Ib-1, Ib-2, Ib-3, Ib-4, Ib-5, or Ib-6, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and STAT are as defined above and as described in embodiments herein, and the variables A, G, G', Q1, Q2, Q3, Q4, R, R', W, X, Y, Z, [ka] , and n are as defined and described in WO 2016 / 197114 and US 2018 / 0147202, each of which is incorporated by reference in its entirety.

[0084] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0085] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0086] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0087] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBM) comprising administering to a mammalian subject the present invention, wherein the FBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FBM is a fibronectin-binding moiety of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein L and STAT are as defined above and described herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1is 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, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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; R 3is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A and may also be at any available carbon or nitrogen atom on ring A (including the ring to which ring B is fused). 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 But R 4 group or R 5 Occupies the -R group position. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 But R 3 Occupies the base position.

[0089] In some embodiments, the compound of formula Ic above has formula I-c' or formula I-c'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-c′ and formula I-c″: STAT, ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0090] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the LBM is represented by formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula Id, L and STAT are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -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, -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 such that ring B is other than imidazo or benzo. [ka] , [ka] , ring B is other than benzo [ka] , ring B is other than benzo [ka] , [ka] Ring B is other than benzo [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 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; 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 the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A and may also be at any available carbon or nitrogen atom on ring A (including the ring to which ring B is fused). 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 But R 4 group or R 5 Occupies the -R group position. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 But R 3 Occupies the base position.

[0092] In some embodiments, the compound of formula Id above has formula I-d' or formula I-d'': [ka] or a pharmaceutically acceptable salt thereof, in formula I-d′ and formula I-d″: STAT, Ring A, L, R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0093] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FB1) comprising administering to a mammalian subject the present invention, wherein the FB1 is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FB1 is a fibronectin-binding moiety of formula Ie: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ie, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Each R 2 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is 1 to 4 independently selected from 6-membered aryl, nitrogen, oxygen, and sulfur. a fused ring 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 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; 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 the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A and may also be at any available carbon or nitrogen atom on ring A (including the ring to which ring B is fused). 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 But R 4 group or R 5 Occupies the -R group position. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 But R 3 Occupies the base position.

[0095] In some embodiments, the compound of formula Ie above has formula I-e' or formula I-e'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-e′ and formula I-e″: STAT, Ring A, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0096] In certain embodiments, the present invention provides a method for treating a cytoplasmic ... [ka] or a pharmaceutically acceptable salt thereof, wherein in formula If, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] 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 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; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments, the compound of formula If has formula If' or formula If': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-f′ and formula I-f″: STAT, ring C, ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m, and p are each as defined above.

[0098] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a leukemia, comprising administering to a patient having the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula Ig, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] a monocyclic or bicyclic ring selected from: R 2 and R 3a each independently represents hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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; 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 the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, the compound of formula Ig has formula I-g' or formula I-g: [ka] [ka] or a pharmaceutically acceptable salt thereof, in formula I-g′ and formula I-g″: STAT, ring C, ring D, L, R 1 , R 2 , R 3a , X 1 , n, m, and p are each as defined above.

[0100] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBM) comprising administering to a mammalian subject the present invention, wherein the FBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FBM is a fibronectin-binding moiety of formula Ih: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ih, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] 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 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; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, the compound of formula Ih above has formula I-h' or formula I-h'': [ka] [ka] or a pharmaceutically acceptable salt thereof, in formula I-h′ and formula I-h″: STAT, ring C, ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n, and p are as defined above.

[0102] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a mammalian subject the present invention, wherein the FBG is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FBG is represented by formula Ii: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula Ii, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] a monocyclic or bicyclic ring selected from: R2 , 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 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 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; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 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 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring; or Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, the compound of formula Ii above has formula I-i' or formula I-i'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-i′ and formula I-i″: STAT, ring C, ring D, L, R 1 , R 2 , R 3a , X 1 , m, n, and p are as defined above.

[0104] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBM) comprising administering to a mammalian subject the present invention, wherein the FBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FBM is a fibronectin-binding moiety of formula Ij: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ij, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3is 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 is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C1~6 an optionally substituted group selected from the group consisting of 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 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, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are 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-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0105] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G (including the ring to which Ring E or Ring G is fused to Ring F).

[0106] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon atom or nitrogen atom on Ring E, Ring F, or Ring G (including the carbon atom where Ring E or Ring G is fused to Ring F).

[0107] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E, Ring F, or Ring G (including the carbon atom where Ring E or Ring G is fused to Ring F).

[0108] In some embodiments, the compound of formula Ij has formula I-j' or formula I-j'': [ka] or a pharmaceutically acceptable salt thereof, in formula I-j′ and formula I-j″: STAT, ring E, ring F, ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0109] In certain embodiments, the present invention provides a method for the treatment of HIV-1-associated ... [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ik, L and STAT are as defined above and as described in embodiments herein, and: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl containing 0-3 nitrogens, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0110] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G (including the ring to which Ring E or Ring G is fused to Ring F).

[0111] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon atom or nitrogen atom on Ring E, Ring F, or Ring G (including the carbon atom where Ring E or Ring G is fused to Ring F).

[0112] In some embodiments, the compound of formula Ik has formula I-k' or formula I-k'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-k′ ​​and formula I-k″: STAT, L, Ring E, Ring F, Ring G, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0113] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a mammalian subject the present invention, wherein the FBG is an E3 ubiquitin ligase (cereblon) binding moiety, such that the FBG is represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II, L and STAT are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 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 is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a 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 carboxyl group, a fused ring selected from a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring H is a fused ring selected from a 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, or 4.

[0114] [ka] is depicted on ring E or ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0115] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0116] [ka] are illustrated on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0117] In some embodiments, the compound of formula II above has the formula II' or the formula II'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-l′ or I-l″: STAT, ring E, ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0118] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBM) comprising administering to a mammalian subject the present invention, wherein the FBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a fibronectin-binding moiety of formula Im: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Im, L and STAT are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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; Ring H is a ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring E is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0119] [ka] is depicted on ring E or ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0120] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0121] [ka] are illustrated on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring E or Ring H (including the carbon atom to which Ring E and Ring H are fused).

[0122] In some embodiments, the compound of formula Im has the formula Im' or formula Im: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-m′ or I-m″: STAT, ring E, ring H, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0123] In some embodiments, the compound of formula Im above has the formula Im-1: [ka] or a pharmaceutically acceptable salt thereof, in formula Im-1: STAT, L, Tamaki E, X 1 , R 1 , R 2 , and m are each as defined above.

[0124] In certain embodiments, the present invention provides a method for treating a cytoplasmic ... [ka] or a pharmaceutically acceptable salt thereof, wherein in the formula In: 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; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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; Ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, or 4.

[0125] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0126] -(R 2 ) m When the attachment points of -(R2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0127] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0128] In some embodiments, the compound of formula In is of formula In' or formula In: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-n′ or I-n″: STAT, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0129] In certain embodiments, the present invention provides compounds of formula Io: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Io: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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; Ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring H is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0130] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0131] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0132] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon atom or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms to which Ring I, Ring J, and Ring K are fused).

[0133] In some embodiments, the compound of formula Io has formula I-o' or formula I-o'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-o′ or I-o″: STAT, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0134] In some embodiments, the compound of formula Io above has formula Io-1: [ka] or a pharmaceutically acceptable salt thereof, in formula Io-1: STAT, L, Ring I, Ring K, X 1 , R 1 , R 2 , and m are each as defined above.

[0135] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a leukemia, amyloid leukemia, or leukemia of formula Io-2 or Io-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas Io-2 and Io-3, L and STAT are as defined above and as described in embodiments herein, and Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and R 4 , R 10 , R 11 , R 15 , W 1 , W 2 and X are as defined in WO 2019 / 099868, the entirety of each of which is incorporated herein by reference.

[0136] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G (including the ring to which Ring E or Ring G is fused to Ring F).

[0137] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon atom or nitrogen atom on Ring E, Ring F, or Ring G (including the carbon atom where Ring E or Ring G is fused to Ring F).

[0138] [ka] is depicted on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G (including the carbon atom where Ring E or Ring G is fused to Ring F).

[0139] X, as defined above and described herein; 1 is a covalent bond, -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

[0140] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X1 is -C(R)-. In some embodiments, X 1 is —C(O)—. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 is —CH(R)—. In some embodiments, X 1 is —CH(CF)—. In some embodiments, X 1 is -P(O)(OR)-. In some embodiments, X 1 is -P(O)(R)-. In some embodiments, X 1 is -P(O)(NR2)-. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1 teeth, [ka] is.

[0141] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0142] X, as defined above and described herein; 2 is a carbon atom or a silicon atom.

[0143] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.

[0144] In some embodiments, X 2 is selected from those illustrated in Table 1 below.

[0145] X, as defined above and described herein; 3is a divalent moiety selected from -CH2-, -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, -CH(R)-, -Si(R2)-, or -O-.

[0146] In some embodiments, X 3 is -CH2-. In some embodiments, X 1 is -C(R)-. In some embodiments, X 3 is -N(R)-. In some embodiments, X 3 In some embodiments, X is —CF—. 3 In some embodiments, X is -CHF-. 3 is -S-. In some embodiments, X 3 is —CH(R)—. In some embodiments, X 3 is —Si(R)—. In some embodiments, X 3 is -O-.

[0147] In some embodiments, X 3 is selected from those illustrated in Table 1 below.

[0148] R as defined above and described herein 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, optionally substituted C 1~4 Aliphatic or R 1 and X 1 or X 4 together with the atoms between them form a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0149] In some embodiments, R 1is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -P(O)(OR). In some embodiments, R 1 is -P(O)(NR2)OR. In some embodiments, R 1 is —P(O)(NR) . In some embodiments, R 1 is —Si(OH)R. In some embodiments, R 1 is —Si(OH)(R). In some embodiments, R 1 is —Si(R). In some embodiments, R 1 is replaced by C 1~4 In some embodiments, R 1 and X 1 or X 4 together with the atoms between them form a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0150] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0151] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group, and the optionally substituted group is C 1~6a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; or two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0152] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted C 1~6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atom between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0153] In some embodiments, R is selected from those depicted in Table 1 below.

[0154] R as defined above and described herein 2 and R 3a each independently represents hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -Si(OH)2R, -Si(OH)R2, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O) R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -OC(O)R, -OC(O)NR2, -O P(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N (R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0155] In some embodiments, R 2 and R 3a are independently hydrogen. In some embodiments, R 2 and R 3a is independently deuterium. In some embodiments, 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 independently -OR. In some embodiments, R 2 and R 3a is independently —Si(OH)R. In some embodiments, R 2 and R 3a are independently —Si(OH)R. In some embodiments, R 2 and R 3ais independently -SR. In some embodiments, R 2 and R 3a is independently -NR2. In some embodiments, R 2 and R 3a is independently -SiR. In some embodiments, R 2 and R 3a is independently -S(O)R. In some embodiments, R 2 and R 3a is independently —S(O)NR. In some embodiments, R 2 and R 3a is independently -S(O)R. In some embodiments, R 2 and R 3a is independently —C(O)R. In some embodiments, R 2 and R 3a is independently —C(O)OR. In some embodiments, R 2 and R 3a is independently —C(O)NR. In some embodiments, R 2 and R 3a is independently —C(O)N(R)OR. In some embodiments, R 2 and R 3a is independently —C(R)N(R)C(O)R. In some embodiments, R 2 and R 3a is independently —C(R)N(R)C(O)NR. In some embodiments, R 2 and R 3a is independently -OC(O)R. In some embodiments, R 2 and R 3a is independently —OC(O)NR. In some embodiments, R 2 and R 3a is independently -OP(O)R. In some embodiments, R 2 and R 3a is independently -OP(O)(OR). In some embodiments, R 2 and R3a is independently -OP(O)(OR)NR. In some embodiments, R 2 and R 3a is independently -OP(O)(NR)-. In some embodiments, R 2 and R 3a is independently —N(R)C(O)OR. In some embodiments, R 2 and R 3a is independently —N(R)C(O)R. In some embodiments, R 2 and R 3a is independently —N(R)C(O)NR. In some embodiments, R 2 and R 3a is independently -NP(O)R. In some embodiments, R 2 and R 3a is independently —N(R)P(O)(OR). In some embodiments, R 2 and R 3a is independently —N(R)P(O)(OR)NR. In some embodiments, R 2 and R 3a is independently —N(R)P(O)(NR). In some embodiments, R 2 and R 3a are independently —N(R)S(O)R.

[0156] In some embodiments, R 2 and R 3a is independently —OH. In some embodiments, R 2 and R 3a is independently -NH. In some embodiments, R 2 and R 3a is independently —CH 2 NH 2 . In some embodiments, R 2 and R 3a is independently -CHNHCOMe. In some embodiments, R 2 and R 3ais independently -CHNHCONHMe. In some embodiments, R 2 and R 3a is independently -NHCOMe. In some embodiments, R 2 and R 3a is independently -NHCONHEt. In some embodiments, R 2 and R 3a is independently -SiMe. In some embodiments, R 2 and R 3a is independently —SiMeOH. In some embodiments, R 2 and R 3a is independently —SiMe(OH). In some embodiments, R 2 and R 3a is independent, [ka] In some embodiments, R 2 and R 3a is independently Br. In some embodiments, R 2 and R 3a is independently Cl. In some embodiments, 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 3a is independently -NHMe. In some embodiments, R 2 and R 3a is independently -NMe. In some embodiments, R 2 and R 3a is independently -NHCOEt. In some embodiments, R 2 and R 3a is independently -CN. In some embodiments, R 2 and R 3ais independently -CHPh. In some embodiments, R 2 and R 3a is independently -NHCO2tBu. In some embodiments, R 2 and R 3a is independently -CO2tBu. In some embodiments, R 2 and R 3a is independently -OMe. In some embodiments, R 2 and R 3a are independently -CF3.

[0157] In some embodiments, R 2 or R 3a is selected from those illustrated in Table 1 below.

[0158] R as defined above and described herein 3 represents hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R )C(O)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O)2NR2, -N(R)P(O)(OR)2, -N(R)P(O )(OR)NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, or -Si(R)3.

[0159] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3is —NO. In some embodiments, R 3 In some embodiments, R 3 is -NR2. In some embodiments, R 3 In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is —C(O)R. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3 is —C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is —OC(O)NR. In some embodiments, R 3 is -OP(O)(OR). In some embodiments, R 3 is -OP(O)(NR). In some embodiments, R 3 is -OP(O)(OR)NR. In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)OR. In some embodiments, R 3 is —N(R)C(O)NR. In some embodiments, R 3 is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R 3 is —N(R)P(O)(OR)NR. In some embodiments, R 3 is -P(O)(OR). In some embodiments, R3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3 is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R 3 is -Si(R)3.

[0160] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0161] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0162] As defined above and described herein, each R 4 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

[0163] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 Ha-R 6 In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is —NO. In some embodiments, R4 In some embodiments, R 4 In some embodiments, R 4 is -NR2. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)NR. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is —C(O)R. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —C(O)NR. In some embodiments, R 4 is —C(O)N(R)OR. In some embodiments, R 4 is -OC(O)R. In some embodiments, R 4 is —OC(O)NR. In some embodiments, R 4 is —N(R)C(O)OR. In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)NR. In some embodiments, R 4 is —N(R)S(O)R. In some embodiments, R 4 is -P(O)(OR). In some embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0164] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0165] In some embodiments, R 4is selected from those illustrated in Table 1 below.

[0166] R as defined above and described herein 5 is hydrogen, deuterium, optionally substituted C 1~4 It is aliphatic, or -CN.

[0167] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is replaced by C 1~4 In some embodiments, R 5 is -CN.

[0168] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0169] As defined above and described herein, each R 6 independently, C 1~6 An optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0170] In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0171] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0172] As defined above and described herein, ring A is [ka] is a bicyclic or tricyclic ring selected from:

[0173] 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.

[0174] 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.

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

[0176] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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;

[0177] In some embodiments, Ring B is a fused 6-membered aryl. In some embodiments, Ring B is a fused 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is a fused 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring B is a fused 5- to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring B is a fused 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] In some embodiments, ring B is [ka] is selected from.

[0184] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0185] As defined above and described herein, Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0186] 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.

[0187] 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.

[0188] In some embodiments, ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0189] In some embodiments, ring C is [ka] is selected from.

[0190] In some embodiments, ring C is [ka] is selected from.

[0191] In some embodiments, ring C is selected from those depicted in Table 1 below.

[0192] As defined above and described herein, ring D is a 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 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;

[0193] In some embodiments, ring D is a 6-membered aryl. In some embodiments, ring D is a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 5-membered to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0194] In some embodiments, ring D is selected from those depicted in Table 1 below.

[0195] As defined above and described herein, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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, wherein each of rings E, F, and G is independently optionally further substituted with 1 to 2 oxo groups.

[0196] In some embodiments, each of ring E, ring F, and ring G is independently a 6-membered aryl. In some embodiments, each of ring E, ring F, and ring G is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of ring E, ring F, and ring G is independently a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups.

[0197] 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.

[0198] 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.

[0199] In some embodiments, each of ring E and ring G is independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are each independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0200] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0201] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0202] 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.

[0203] 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.

[0204] In some embodiments, ring E, ring F, and ring G are selected from those depicted in Table 1 below.

[0205] As defined above and described herein, Ring H is a ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups.

[0206] In some embodiments, ring H is selected from boron, nitrogen, oxygen, silicon, or sulfur. and wherein ring H is optionally further substituted with 1 to 2 oxo groups.

[0207] 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.

[0208] In some embodiments, ring E and ring H are [ka] is.

[0209] In some embodiments, ring E and ring H are selected from those depicted in Table 1 below.

[0210] As defined above and described herein, each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl 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.

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

[0212] 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 independently: [ka] is.

[0213] 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.

[0214] As defined above and described herein, ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein ring H is optionally further substituted with 1 to 2 oxo groups.

[0215] In some embodiments, ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring K is a 6- to 12-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

[0216] 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.

[0217] In some embodiments, ring I, ring J, and ring K are [ka] is.

[0218] In some embodiments, ring I, ring J, and ring K are selected from those depicted in Table 1 below.

[0219] As defined above and described herein, L 1 is a covalent bond, or C 1~3a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-;

[0220] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~3 In some embodiments, L 1 is -CH-. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D)2-. In some embodiments, L 1 is -CHCH-. In some embodiments, L 1 In some embodiments, L 1 is -CHNR-. In some embodiments, L 1 or -O-. In some embodiments, L 1 is —CH2O—. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1 is —C(O)O—. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is —S(O)—. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -NRS(O)-. In some embodiments, L 1 is -S(O)NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is -C(O)NR-.

[0221] In some embodiments, ring L 1 is selected from those illustrated in Table 1 below.

[0222] As defined above and described herein, [ka] is a single or double bond.

[0223] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0224] In some embodiments, [ka] is selected from those illustrated in Table 1 below.

[0225] 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.

[0226] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[0227] In some embodiments, m is selected from those depicted in Table 1 below.

[0228] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0229] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0230] In some embodiments, n is selected from those depicted in Table 1 below.

[0231] As defined above and described herein, p is 0 or 1.

[0232] In some embodiments, p is 0. In some embodiments, p is 1.

[0233] In some embodiments, p is selected from those depicted in Table 1 below.

[0234] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0235] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula Ip-1, Ip-2, or Ip-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Ip-1, Ip-2, and Ip-3, L and STAT are as defined above and described herein, and variable R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 ,X, [ka] each of n is as defined in WO 2017 / 197051, which is incorporated herein by reference in its entirety; and [ka] is R as defined in WO 2017 / 197051 1 , R 1 and R 2 or R 17 To, R 12 The binding site of [ka] But R 12 Occupy the position of the substituent.

[0236] In some embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula Iq-1, Iq-2, Iq-3, or Iq-4, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas Iq-1, Iq-2, Iq-3, and Iq-4, L and STAT 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] each of n is as defined in WO 2018 / 237026, 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 binding site, resulting in [ka] But R 12 Occupy the position of the substituent.

[0237] In some embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula Ir-1 or Ir-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Ir-1 and Ir-3, L and STAT are as defined above and described herein, and variable R 1 , R 14 , and R 16 each of which is as defined in WO 2018 / 237026, 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 binding site, resulting in [ka] But R 12 Occupy the position of the substituent.

[0238] In certain embodiments, the present invention provides a polypeptide wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing a polypeptide of formula Is-1, Is-2, Is-3, Is-4, Is-5, Is-6, Is-7, or Is-8: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas Is-1, Is-2, Is-3, Is-4, Is-5, Is-6, Is-7, and Is-8, L and STAT are as defined above and as described in embodiments herein, and the variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8, A, L, x, y, and [ka] each as described and defined in WO 2017 / 161119, the entirety of each of which is incorporated herein by reference.

[0239] In certain embodiments, the present invention provides a method for treating a cereblon-associated ubiquitin ligase (LBM) comprising administering to a mammalian subject the present invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the LBM has the formula It: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula It, L and STAT are as defined above and as described in embodiments herein, and each of the variables A, B, C, W, X, Y, and Z are as described and defined in U.S. Pat. No. 5,721,246, each of which in its entirety is incorporated herein. and incorporated herein by reference.

[0240] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, such that the LBM has the formula It-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula It-1, L and STAT are as defined above and in embodiments herein, and each of the variables R1, R2, and n are as described and defined in WO 2019 / 043214, the entirety of each of which is incorporated herein by reference.

[0241] In some embodiments, the LBM comprises an IAP E3 ubiquitin ligase binding moiety as described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, e.g., [ka] [ka] etc., where [ka] is attached to a modifiable carbon atom, oxygen atom, nitrogen atom, or sulfur atom.

[0242] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety, represented by formula Iu-1, Iu-2, Iu-3, Iu-4, or Iu-5, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas Iu-1, Iu-2, Iu-3, Iu-4, and Iu-5, L and STAT are as defined above and as described in embodiments herein, and the variable R 1’ , R 2’ , R 3’ , X, and X′ are each as defined and described in WO 2013 / 106643 and US 2014 / 0356322, each of which is incorporated by reference in its entirety.

[0243] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety, represented by formula Iv-1, Iv-2, Iv-3, Iv-4, Iv-5, or Iv-6, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Iv-1, Iv-2, Iv-3, Iv-4, Iv-5 and Iv-6, L and STAT are as defined above and as described in embodiments herein, and variable R 1’ , R 2’ , R 3’ , R5, R6, R7, R9, R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X', Y, Z1, Z2, Z3, Z4, and o are as defined and described in WO 2016 / 149668 and US 2016 / 0272639, each of which is incorporated by reference in its entirety.

[0244] As used herein, the bracket illustration around any LBM [ka] teeth, [ka] This means that the moiety is covalently attached to the LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For clarity, by way of example, such available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the structure of the following LBM compound are illustrated below, where each wavy bond represents the [ka] Show the attachment points to: [ka] [ka] .

[0245] In certain embodiments, the present invention provides a method for treating a VHL E3 ubiquitin ligase-binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase-binding moiety, represented by formula Iw-1, Iw-2, or Iw-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Iw-1, Iw-2, and Iw-3, L and STAT are as defined above and as described in embodiments herein, and variable R p , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 Each of 1, 2, and 3 is as defined and described in WO 2016 / 118666 and US 2016 / 0214972, each of which is incorporated by reference in its entirety.

[0246] In certain embodiments, the present invention provides that the LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety, thereby representing Formula Ix-1, Ix-2, Ix-3, Ix-4, Ix-5, Ix-6, or Ix-7, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas Ix-1, Ix-2, Ix-3, Ix-4, Ix-5, Ix-6, and Ix-7, L and STAT are as defined above and as described in embodiments herein, and variable A 1 , A 2 , A 3 , R 5 , G and Z are as defined and described in WO 2017 / 176958.

[0247] In certain embodiments, the present invention provides a method for the preparation of CRBN E3 ubiquitin ligase-binding moieties, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is represented by formula I-x'-1, I-x''-1, I-x'-2, I-x''-2, I-x'-3, I-x''-3, I-x'-4, I-x''-4, I-x'-7, or I-x''-7, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-x'-1, I-x''-1, I-x'-2, I-x''-2, I-x'-3, I-x''-3, I-x'-4, I-x''-4, I-x'-7 and I-x''-7, L and STAT are as defined above and as described in embodiments herein, and variable A 1 , A 2 , A 3 , R 5 , G and Z are each as defined and described in WO 2017 / 176958, the entirety of which is incorporated herein by reference.

[0248] In certain embodiments, the present invention provides that the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby representing the formula Iy-1, Iy-2, Iy-3, Iy-4, Iy-5, Iy-6, Iy-7, Iy-8, Iy-9, Iy-10, Iy-11, Iy-12, Iy-13, Iy-14, Iy-15, Iy-16, Iy-17, or Iy-18, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Iy-1, Iy-2, Iy-3, Iy-4, Iy-5, Iy-6, Iy-7, Iy-8, Iy-9, Iy-10, Iy-11, Iy-12, Iy-13, Iy-14, Iy-15, Iy-16, Iy-17, and Iy-18, L and STAT are as defined above and as described in embodiments herein, and the variables R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R 6’ , R 7’ , R8’ , R 9’ , R 10’ , R 11’ , R 12’ , R 1’’ , A, A', A'', X, Y, and Z are as defined and described in WO 2017 / 011371 and US 2017 / 0008904, each of which is incorporated by reference in its entirety.

[0249] In certain embodiments, the present invention provides a method for treating IAP E3 ubiquitin ligase-binding moieties, whereby the LBM is an IAP E3 ubiquitin ligase-binding moiety, represented by the formula Iz-1, Iz-2, Iz-3, or Iz-4, respectively. -z-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Iz-1, Iz-2, Iz-3, and Iz-4, L and STAT are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each as defined and described in WO 2017 / 011590 and US 2017 / 0037004, each of which is incorporated by reference in its entirety.

[0250] In certain embodiments, the present invention provides a method for the production of LBMs comprising administering to a mammalian subject the invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; whereby the LBM is represented by Formula I-aa-1, I-aa-2, or I-aa-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aa-1, I-aa-2, and I-aa-3, L and STAT are as defined above and as described in embodiments herein, and X 1 , X 2a , and X 3a each independently represents a covalent bond, —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 4 and X 5 each independently is a divalent moiety and is -CH2-, -C(O)-, -C(S)-, or [ka] Selected from; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic; R 2 , R 3b , and R 4a each independently represents hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5a is hydrogen or C 1~6 It is aliphatic; Each R 6 independently, C 1~6 Independently from aliphatic, phenyl, nitrogen, oxygen, and sulfur an optionally substituted group selected from the group consisting of a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 selected heteroatoms, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A a is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or an 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring C a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0251] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the LBM is represented by formula I-aa'-1 or I-aa''-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-aa'-1 and I-aa''-1, STAT, L, ring A a , X 1 , X 2a , X 3a , R 1 , R 2 and m is as described above.

[0252] X, as defined above and described herein; 1 , X 2a , and X 3a each independently represents a covalent bond, —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from

[0253] In some embodiments, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0254] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0255] In some embodiments, X 2a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0256] In some embodiments, X 2a is selected from those illustrated in Table 1 below.

[0257] In some embodiments, X 3a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0258] In some embodiments, X 3a is selected from those illustrated in Table 1 below.

[0259] X, as defined above and described herein; 4 and X 5 each independently is —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from

[0260] In some embodiments, X 4a is -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0261] In some embodiments, X 4a is selected from those illustrated in Table 1 below.

[0262] In some embodiments, X 5a is -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0263] In some embodiments, X 5a is selected from those illustrated in Table 1 below.

[0264] R as defined above and described herein 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic.

[0265] In some embodiments, R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 It is aliphatic.

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

[0267] R as defined above and described herein 2 , R 3b , and R 4a each independently represents hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0268] In some embodiments, R 2 is hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0269] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0270] In some embodiments, R 3b is hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0271] In some embodiments, R 3b is methyl.

[0272] In some embodiments, R 3b is selected from those illustrated in Table 1 below.

[0273] In some embodiments, R 4a is hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0274] In some embodiments, R 4a is methyl.

[0275] In some embodiments, R 4a is selected from those illustrated in Table 1 below.

[0276] R as defined above and described herein 5a is hydrogen or C 1~6 It is aliphatic.

[0277] In some embodiments, R 5a is t-butyl.

[0278] In some embodiments, R 5a is selected from those illustrated in Table 1 below.

[0279] As defined above and described herein, each R 6 independently, C 1~6 An optionally substituted group selected from the group consisting of 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.

[0280] In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0281] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0282] Ring A, as defined above and described herein a is a fused ring selected from a 6-membered aryl containing 0 to 2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0283] In some embodiments, ring A a is a fused 6-membered aryl containing 0 to 2 nitrogen atoms. a is a fused 5- to 7-membered partially saturated carbocyclyl. a is nitrogen, oxygen or sulfur? In some embodiments, ring A is a fused 5- to 7-membered partially saturated heterocyclyl having 1 to 2 heteroatoms independently selected from a is a fused 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0284] In some embodiments, ring A a is a fused phenyl.

[0285] In some embodiments, ring A a is selected from those illustrated in Table 1 below.

[0286] Ring B, as defined above and described herein a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or an 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0287] In some embodiments, ring B a is a 6-membered aryl containing 0 to 2 nitrogen atoms. a is an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0288] In some embodiments, ring B a teeth, [ka] is.

[0289] In some embodiments, ring B a is selected from those illustrated in Table 1 below.

[0290] As defined above and described herein, ring C a is selected from a 6-membered aryl containing 0 to 2 nitrogen atoms or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0291] In some embodiments, ring C a is a 6-membered aryl containing 0 to 2 nitrogen atoms. In some embodiments, ring C a is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0292] In some embodiments, ring C a teeth, [ka] is.

[0293] In some embodiments, ring C a is selected from those illustrated in Table 1 below.

[0294] As defined above and described herein, m is 0, 1, 2, 3, or 4.

[0295] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0296] In some embodiments, m is selected from those depicted in Table 1 below.

[0297] In some embodiments, o is selected from those depicted in Table 1 below.

[0298] As defined above and described herein, o is 0, 1, 2, 3, or 4.

[0299] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0300] In some embodiments, o is selected from those depicted in Table 1 below.

[0301] As defined above and described herein, q is 0, 1, 2, 3, or 4.

[0302] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0303] In some embodiments, q is selected from those depicted in Table 1 below.

[0304] As defined above and described herein, each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0305] In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen, optionally together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0306] In some embodiments, R is selected from those depicted in Table 1 below.

[0307] In certain embodiments, the present invention provides a method for treating a VHL-associated leukemia, wherein the LBM is a VHL binding moiety, whereby Formula I-ab: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-ab, L and STAT are as defined above and as described in embodiments herein, and variables R, R 10 , R 11 , R 14a , and R 15 each of which is incorporated herein by reference in its entirety. 2017 / 0327469, the entireties of which are incorporated herein by reference.

[0308] In certain embodiments, the present invention provides compounds wherein the LBM is a VHL binding moiety, thereby having formula I-ac-1 or I-ac-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-ac-1 and I-ac-2, L and STAT are as defined above and as described in embodiments herein, and variables X, W, 3 , W 5 , R9, R 10 , R 11 , R 14a , R 14b , R 15 , R 16 Each of , and o is as described and defined in WO 2017 / 030814, WO 2016 / 118666, and US 2017 / 0327469, each of which is incorporated by reference in its entirety.

[0309] In certain embodiments, the present invention provides compounds wherein the LBM is an IAP binding moiety, whereby the LBM has the formula I-ad: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I-ad, L and STAT are as defined above and as described in embodiments herein, and variables W, Y, Z, R 1 , R 2 , R 3 , R 4 , and R 5 each as described and defined in WO 2014 / 044622, US 2015 / 0225449, WO 2015 / 071393, and US 2016 / 0272596, each of which is incorporated by reference in its entirety.

[0310] In certain embodiments, the present invention provides compounds wherein the LBM is an MDM2 binding moiety, whereby the compound has formula I-ae: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Hines, J. et al., Cancer Res. (DOI: 10.1158 / 0008-5472.CAN-18-2918), each of which is incorporated herein by reference in its entirety.

[0311] In certain embodiments, the present invention provides a compound wherein the LBM is a DCAF16 binding moiety, whereby the compound has the formula I-af: [ka] or a pharmaceutically acceptable salt thereof, ang, X. et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 443804), each of which is incorporated herein by reference in its entirety.

[0312] In certain embodiments, the present invention provides compounds wherein the LBM is an RNF114 binding moiety, whereby the compound has formula I-ag: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, JNet al., bioRxiv (doi: https: / / doi.org / 10.1101 / 436998), each of which is incorporated herein by reference in its entirety.

[0313] In certain embodiments, the present invention provides compounds wherein the LBM is an RNF4 binding moiety, whereby the compound has formula I-ah: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Ward, CC, et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125), each of which is incorporated herein by reference in its entirety.

[0314] In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has the formula I-aay-1 or I-aay-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aay-1 and I-aay-2, L and STAT are as defined above and as described in embodiments herein, and the variable R 1 , R 2 , R 3 , X, and Y are each as defined and described in WO 2019 / 084026, the entirety of each of which is incorporated herein by reference.

[0315] In certain embodiments, the present invention provides compounds wherein the LBM is a VHL binding moiety, thereby having formula I-aaz-1 or I-aaz-2: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aaz-1 and I-aaz-2, L and STAT are as defined above and as described in embodiments herein, and variable R 1 , R 3 and Y are each as defined and described in WO 2019 / 084030, the entirety of each of which is incorporated herein by reference.

[0316] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBG) comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aaaa-1, I-aaaa-2, I-aaaa-3, and I-aaaa-4, L and STAT are as defined above and described herein, and variable R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 and each of X is as defined in WO 2019 / 099868, which is incorporated herein by reference in its entirety; and [ka] is R as defined in WO 2018 / 237026 17or R 16 To, R 12 binding site, resulting in [ka] But this R 12 Occupy the position of the substituent.

[0317] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0318] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, thereby providing a ubiquitin ligase having the formula I-bbbb: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb, L and STAT are as defined above and as described in embodiments herein, each X 1 are independently -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] and; X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] and; Z 1 and Z 2 are independently a carbon atom or a nitrogen atom; Ring A x is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L x is a covalent bond, or C 1~3 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-; Each R 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(O)N(R)OR, —OC(O)R, —OC(O)NR2, —C(S)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, —Si(OR)R2, and —SiR3; or 2 R's x the groups optionally taken together form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R y teeth, [ka] or hydrogen; Ring B xis a 4- to 10-membered saturated or partially unsaturated, monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is optionally further substituted with 1 to 2 oxo groups; Each R w 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(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, and -SiR3; Each R z independently, C 1~6 selected from optionally substituted groups selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [ka] is a single or double bond; x is 0, 1, 2, 3 or 4; y is 0, 1, or 2; and w is 0, 1, 2, 3 or 4.

[0319] As defined above and described herein, each X 1 are independently -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] is.

[0320] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 is —O—. In some embodiments, X 1 is -NR-. In some embodiments, X 1 In some embodiments, X is —CF—. 1 teeth [ka] In some embodiments, X 1 is —C(O)—. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 teeth [ka] is.

[0321] In certain embodiments, X 1 is selected from those shown in the compounds of Table 1.

[0322] As defined above and described herein, X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0323] In some embodiments, X 2and X 3 is independently -CH-. In some embodiments, X 2 and X 3 is independently —C(O)—. In some embodiments, X 2 and X 3 is independently -C(S)-. In some embodiments, X 2 and X 3 is independent, [ka] is.

[0324] In certain embodiments, X 2 and X 3 are independently selected from those shown in the compounds of Table 1.

[0325] As defined above and described herein, Z 1 and Z 2 are independently carbon atoms or nitrogen atoms.

[0326] In some embodiments, Z 1 and Z 2 are independently carbon atoms. In some embodiments, Z 1 and Z 2 are independently carbon atoms.

[0327] In certain embodiments, Z 1 and Z 2 are independently selected from those shown in the compounds of Table 1.

[0328] Ring A, as defined above and described herein x is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0329] In some embodiments, ring A xIn some embodiments, ring A is benzo. x is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0330] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] is.

[0331] In certain embodiments, ring A x is selected from those shown in the compounds of Table 1.

[0332] As defined above and described herein, L x is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0333] In some embodiments, L x is a covalent bond. In some embodiments, L x is C 1~3wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0334] In some embodiments, L x is -C(O)-.

[0335] In certain embodiments, L x is selected from those shown in the compounds of Table 1.

[0336] As defined above and described herein, 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(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3, or two R x are optionally joined together to form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0337] In some embodiments, R x is hydrogen. In some embodiments, R x is deuterium. In some embodiments, R x is R z In some embodiments, R x is halogen. In some embodiments, Rx is -CN. In some embodiments, R x is —NO. In some embodiments, R x In some embodiments, R x In some embodiments, R x is -NR2. In some embodiments, R x is —S(O)R. In some embodiments, R x is —S(O)NR. In some embodiments, R x is -S(O)R. In some embodiments, R x is -CF2R. In some embodiments, R x is —CF. In some embodiments, R x is -CR2(OR). In some embodiments, R x is -CR2(NR2). In some embodiments, R x is —C(O)R. In some embodiments, R x is —C(O)OR. In some embodiments, R x is —C(O)NR. In some embodiments, R x is —C(O)N(R)OR. In some embodiments, R x is -OC(O)R. In some embodiments, R x is —OC(O)NR. In some embodiments, R x is —C(S)NR. In some embodiments, R x is —N(R)C(O)OR. In some embodiments, R x is —N(R)C(O)R. In some embodiments, R x is —N(R)C(O)NR. In some embodiments, R x is —N(R)S(O)R. In some embodiments, R x is -OP(O)R. In some embodiments, R xis -OP(O)(OR). In some embodiments, R x is -OP(O)(OR)NR. In some embodiments, R x is -OP(O)(NR). In some embodiments, R x is —Si(OR)R. In some embodiments, R x is -SiR. In some embodiments, two R x are optionally joined together to form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0338] In some embodiments, R x is fluoro. In some embodiments, R x is bromo. In some embodiments, R x is methyl. In some embodiments, R x is —OH. In some embodiments, R x is -NH2. In some embodiments, R x is -NHCH3. In some embodiments, R x is —N(CH). In some embodiments, R x is —NHCH(CH). In some embodiments, R x is —NHSO2CH3. In some embodiments, R x is —CHOH. In some embodiments, R x is —CH 2 NH 2 . In some embodiments, R x is —C(O)NH. In some embodiments, R x is —C(O)NHCH. In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] is.

[0339] In certain embodiments, each R x are independently selected from those shown in the compounds of Table 1.

[0340] As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group, which optionally substituted group is C 1~6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally taken together with the atoms between them form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0341] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen, together with atoms between them, optionally form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0342] As defined above and described herein, R y teeth, [ka] or hydrogen.

[0343] In some embodiments, R y teeth, [ka] In some embodiments, R y is hydrogen.

[0344] In certain embodiments, R y is selected from those shown in the compounds of Table 1.

[0345] As defined above and described herein, ring B x is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic ring, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is further optionally substituted with 1 to 2 oxo groups.

[0346] In some embodiments, ring B x is phenyl. In some embodiments, ring B x is a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. x is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B x is further optionally substituted with 1 to 2 oxo groups.

[0347] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] is.

[0348] In certain embodiments, ring B x is selected from those shown in the compounds of Table 1.

[0349] As defined above and described herein, each R w 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(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, and —SiR3.

[0350] In some embodiments, R w is hydrogen. In some embodiments, R wis deuterium. In some embodiments, R w is R z In some embodiments, R w is halogen. In some embodiments, R w is -CN. In some embodiments, R w is —NO. In some embodiments, R w In some embodiments, R w In some embodiments, R w is -NR2. In some embodiments, R w is —S(O)R. In some embodiments, R w is —S(O)NR. In some embodiments, R w is -S(O)R. In some embodiments, R w is -CF2R. In some embodiments, R w is —CF. In some embodiments, R w is -CR2(OR). In some embodiments, R w is -CR2(NR2). In some embodiments, R w is —C(O)R. In some embodiments, R w is —C(O)OR. In some embodiments, R w is —C(O)NR. In some embodiments, R w is —C(O)N(R)OR. In some embodiments, R w is -OC(O)R. In some embodiments, R w is —OC(O)NR. In some embodiments, R w is —N(R)C(O)OR. In some embodiments, R w is —N(R)C(O)R. In some embodiments, R w is —N(R)C(O)NR. In some embodiments, R w is —N(R)S(O)R. In some embodiments, Rw is -OP(O)R. In some embodiments, R w is -OP(O)(OR). In some embodiments, R w is -OP(O)(OR)NR. In some embodiments, R w is -OP(O)(NR). In some embodiments, R w is -SiR3.

[0351] In certain embodiments, R w is selected from those shown in the compounds of Table 1.

[0352] As defined above and described herein, each R z independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0353] In some embodiments, R z is replaced by C 1~6 In some embodiments, R z is optionally substituted phenyl. In some embodiments, R z is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R z is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0354] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] is.

[0355] In certain embodiments, R z is selected from those shown in the compounds of Table 1.

[0356] As defined above and described herein, [ka] is a single or double bond.

[0357] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0358] In certain embodiments, [ka] is selected from those shown in the compounds of Table 1.

[0359] As defined above and described herein, w is 0, 1, 2, 3, or 4.

[0360] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0361] In certain embodiments, w is selected from those shown in the compounds of Table 1.

[0362] As defined above and described herein, x is 0, 1, 2, 3, or 4.

[0363] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, m is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0364] In certain embodiments, x is selected from those shown in the compounds of Table 1.

[0365] As defined above and described herein, y is 0, 1, or 2.

[0366] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0367] In certain embodiments, y is selected from those shown in the compounds of Table 1.

[0368] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-1, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0369] In some embodiments, the present invention provides a compound comprising ring A x is imidazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-2, STAT, L, L x , and R yEach of the is as defined above and described in embodiments herein, both alone and in combination.

[0370] In some embodiments, the present invention provides a compound comprising ring A x is imidazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-3, STAT, L, L x , and R y Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0371] In some embodiments, the present invention provides a compound comprising ring A x is oxazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-4, each of STAT and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0372] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 0, and X 2 and X3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-5: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-5, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0373] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -O- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-6: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-6, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0374] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -NR- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-7: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-7, STAT, L, L x , R, R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0375] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -CF2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-8: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-8, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0376] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 but [ka] and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-9: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-9, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0377] In some embodiments, the present invention provides a compound comprising ring A x is pyridyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-10: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-10, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0378] In some embodiments, the present invention provides a compound comprising ring A x is pyridyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-11: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-11, STAT, L, L x , R x , Ry and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0379] In some embodiments, the present invention provides a compound wherein ring A is benzo, y is 1, and X 1 , X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-bbbb-12: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-12, STAT, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0380] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0381] In some embodiments, the LBM is selected from those in Table 1.

[0382] In certain embodiments, the present invention provides a compound wherein the LBM is an RPN13 binding moiety, whereby the compound has formula I-cccc: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cccc, L and STAT are as defined above and in embodiments herein, and each of variables A, Y, and Z are as described and defined in WO 2019 / 165229, the entirety of each of which is incorporated herein by reference.

[0383] In certain embodiments, the present invention provides a method for the preparation of a Ubr1-binding moiety, wherein the LBM is a Ubr1-binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi: 10.1074 / jbc.AC119.010790, each of which is incorporated by reference herein in its entirety, whereby the LBM has the formula I-dddd-1 or I-dddd-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-dddd-1 and I-dddd-2, L and STAT are as defined above and as described in embodiments herein.

[0384] In certain embodiments, the present invention provides a compound wherein the LBM is a CRBN binding moiety, whereby the compound has formula I-eeee: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-eeee, L and STAT are as defined above and in embodiments herein, and each of the variables R1, R2, R3, R4, R5, Q, X, and n are as described and defined in US 2019 / 276474, the entirety of each of which is incorporated herein by reference.

[0385] In certain embodiments, the present invention provides a method for producing a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety of formula I-ffff-1, I-ffff-2, I-ffff-3, or I-ffff-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-ffff-1, I-ffff-2, I-ffff-3 and I-ffff-4, L and STAT are as defined above and as described in embodiments herein, and variables Y, A 1 , and A 3 each as described and defined in WO 2019 / 236483, the entirety of each of which is incorporated herein by reference. Decomposition induction part (DIM)

[0386] In certain embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula II, L and STAT are as described above and herein, and DIM is a degradation-inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom.

[0387] In some embodiments, the DIM is an LBM as described above and herein. In some embodiments, the DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to one or more members of the STAT protein family (i.e., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) is achieved by the action of a lysine mimetic. In some embodiments, when a compound of Formula II binds to STAT1, the lysine mimetic moiety causes ubiquitination, thereby marking STAT1 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT2, the lysine mimetic moiety causes ubiquitination, thereby marking STAT2 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT3, the lysine mimetic moiety undergoes ubiquitination, thereby marking STAT3 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT4, the lysine mimetic moiety undergoes ubiquitination, thereby marking STAT4 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT5A, the lysine mimetic moiety undergoes ubiquitination, thereby marking STAT5A for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT5B, the lysine mimetic moiety undergoes ubiquitination, thereby marking STAT5B for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT6, the lysine mimetic moiety undergoes ubiquitination, thereby marking STAT6 for degradation via the ubiquitin-proteasome pathway (UPP).

[0388] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] is.

[0389] In some embodiments, the DIM is selected from those depicted in Table 1A below.

[0390] In some embodiments, the present invention provides a compound of formula I having formula II-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula II-a, each of STAT and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0391] In some embodiments, the present invention provides a compound of formula I having formula II-b: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula II-b, each of STAT and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0392] In some embodiments, the present invention provides a compound of formula I having formula II-c: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula II-c, each of STAT and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0393] In certain embodiments, the present invention provides a method for treating rhodamine-containing ... [ka] [ka] which give the compounds of formula II-d-1, II-d-2, or II-d-3, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas II-d-1, II-d-2, and II-d-3, L and STAT are as defined above and as described in embodiments herein, and variable R 1 , R 4 , R 5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496, the entirety of each of which is incorporated herein by reference. hydrogen atom

[0394] In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent attachment of ubiquitin to one or more members of the STAT protein family (i.e., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) is achieved through a provided compound in which DIM is a hydrogen atom. In some embodiments, when a compound of Formula II binds to STAT1, the moiety that is hydrogen causes ubiquitination, thereby marking STAT1 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT2, the moiety that is hydrogen causes ubiquitination, thereby marking STAT2 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT3, the moiety that is hydrogen causes ubiquitination, thereby marking STAT3 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT4, the moieties that are hydrogen cause ubiquitination, thereby marking STAT4 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT5A, the moieties that are hydrogen cause ubiquitination, thereby marking STAT5A for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT5B, the moieties that are hydrogen cause ubiquitination, thereby marking STAT5B for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT6, the moieties that are hydrogen cause ubiquitination, thereby marking STAT6 for the ubiquitin proteasome (UPP).

[0395] In some embodiments, the DIM is selected from those depicted in Table 1A below.

[0396] In some embodiments, the present invention provides a compound of formula II-d-4, wherein DIM is a hydrogen atom, and thereby the compound of formula II-d-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-d-4, each of STAT and L, both alone and in combination, is as defined above and as described in embodiments herein. STAT binding part (STAT)

[0397] As defined above and described herein, a STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.

[0398] In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT1. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT2. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT3. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT4. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT5A. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT5B. In some embodiments, the STAT is a STAT binding moiety capable of binding to STAT6.

[0399] As defined herein and described below, formulas may be expressed using square brackets, e.g., [ka] where L is attached to a modifiable carbon, oxygen, or nitrogen atom in STAT, and includes substitution or replacement of the defined group on STAT.

[0400] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-ai or II-e: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-ai and II-e, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables R1, R2, R3, R4, R5, and R6 are as described and defined in US 2004 / 0138189, the entirety of each of which is incorporated herein by reference.

[0401] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-aj or II-f: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-aj and II-f, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables R0, R2, R3, and R4 are as described and defined in US 2005 / 0277680, the entirety of each of which is incorporated herein by reference.

[0402] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-ak or II-g: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-ak and II-g, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables R1, R2, R3, R6, AA, and n are as described and defined in US 2008 / 0139456, the entirety of each of which is incorporated herein by reference.

[0403] In some embodiments, the present invention relates to a compound in which the STAT is a compound described in US 2006 / 0247318, such as [ka] or a pharmaceutically acceptable salt thereof, wherein the STAT3 binding moiety is selected from the group consisting of: [ka] is attached to a modifiable carbon or oxygen atom.

[0404] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-al or II-i: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-a1 and II-i, L and LBM or DIM are as defined above and in embodiments herein, and the one or more amino acids replaced with structural analogs are as described and defined in US 2007 / 0010428, the entirety of each of which is incorporated herein by reference.

[0405] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-am or II-j: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-am and II-j, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables A, B, Z, n, and m are as described and defined in WO 2007 / 042912 and US 7,786,142, each of which is incorporated by reference in its entirety.

[0406] In some embodiments, the present invention provides a method for treating STAT-associated steroid deficiencies, including the treatment of STAT-associated steroid deficiencies, comprising administering to a subject a therapeutically effective amount of a STAT-associated steroid deficiency, such as ... 263435 (shown in Figure 48), HL2-006-1 (shown in Figure 13), HL2-006-2 (shown in Figure 14), HL2-006-3 (shown in Figure 15), HL2-006-4 (shown in Figure 16), HL2-006-5 (shown in Figure 17), HL2-011-1 (shown in Figure 18), HL2-011-2 (shown in Figure 19), HL2-01 1-3 (shown in Figure 20), HL2-011-4 (shown in FIG. 21), HL2-011-5 (shown in FIG. 22), BG2069-1 (shown in FIG. 23), HL2-011-6 (shown in FIG. 24), HL2-011-7 (shown in FIG. 25), HL2-005 (shown in FIG. 26), HL2-OO3 (shown in FIG. 27), BG2066 (shown in FIG. 28), BG2074 (shown in FIG. 29), BG300 4 (shown in Figure 30), BG3006A (shown in Figure 31), BG3006B (shown in Figure 32), BG3006D (shown in Figure 33), BG3009 (shown in Figure 34), RPM381 (shown in Figure 35), RPM384 (shown in Figure 35), RPM385 (shown in Figure 35), RPM405 (shown in Figure 36), RPM411 (shown in Figure 36), R and RPM444 (shown in Figure 44), RPM448 (shown in Figure 44), RPM445 (shown in Figure 45), RPM447 (shown in Figure 45), RPM452 (shown in Figure 46), and RPM202, or a pharmaceutically acceptable salt thereof, wherein [ka] is attached to a modifiable carbon atom, oxygen atom, nitrogen atom, or sulfur atom.

[0407] In certain embodiments, the present invention provides compounds wherein the STAT is a STAT3 or STAT5 binding moiety, whereby the compound has formula I-an or II-k: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-an and II-k, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables R1, R2, X, and Z are as described and defined in U.S. Pat. No. 7,960,434, the entirety of each of which is incorporated herein by reference.

[0408] In some embodiments, the present invention relates to a compound in which the STAT is a compound described in US 2006 / 0247318, such as [ka] or a pharmaceutically acceptable salt thereof, wherein the STAT3 binding moiety is selected from the group consisting of: [ka] is attached to a modifiable carbon, nitrogen, or oxygen atom.

[0409] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 or STAT5 binding moiety, whereby the compound has formula I-ap or II-m: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-ap and II-m, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 Each of A, X1, and Y is as described and defined in US 8,263,599, the entirety of each of which is incorporated herein by reference.

[0410] In certain embodiments, the present invention provides compounds wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-aq or II-n: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-aq and II-n, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 1’ , R 2 , R 3 , R 6 Each of AA, AA, and n is as described and defined in WO 2008 / 067270, the entirety of each of which is incorporated herein by reference.

[0411] In certain embodiments, the invention provides a STAT, wherein the STAT is a STAT1, STAT3, or STAT5 binding moiety, thereby representing a STAT1, STAT3, or STAT5 binding moiety of formula I-ar-1, I-ar-2, I-ar-3, I-ar-4, II-o-1, II-o-2, II-o-3, or II-o-4: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-ar-1, I-ar-2, I-ar-3, I-ar-4, II-o-1, II-o-2, II-o-3, and II-o-4, L and LBM or DIM are as defined above and as described in embodiments herein, and the variables R, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 Each of x, x, and y is as described and defined in WO 2008 / 156644 and US 2011 / 0144043, each of which is incorporated by reference herein in its entirety.

[0412] In some embodiments, the invention provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, wherein STAT is a STAT3 binding moiety selected from the compounds described in WO 2009 / 032338, e.g., apratoxin A, apratoxin B, apratoxin C, E-dehydroaplatoxin A, apratoxin D, apratoxin E, and the described analogs thereof; [ka] is attached to a modifiable carbon, nitrogen, or oxygen atom.

[0413] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-as or II-p: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-as and II-p, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each of A, W, and X is as described and defined in WO 2010 / 004761 and US 8,446,290, each of which is incorporated by reference herein in its entirety.

[0414] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-at or II-q: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-at and II-q, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables Ro, R2, R3, R4, and n are as described and defined in WO 2010 / 005807 and US 8,143,412, each of which is incorporated by reference in its entirety.

[0415] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-au or II-r: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-au and II-r, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3 , R 4 Each of X, X, and Y is as described and defined in WO 2010 / 077589 and US 2011 / 0319362, each of which is incorporated by reference herein in its entirety.

[0416] In certain embodiments, the present invention provides a method for treating STAT3-related disorders, wherein the STAT is a STAT3 binding moiety, such as a STAT3-related disorder, represented by Formula II-r'-1, II-r'-2, II-r'-3, or II-r'-4: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in embodiments herein; and Ring M is an optionally substituted ring selected from phenyl, naphthyl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclyl, and a 5- to 11-membered saturated or partially unsaturated heterocyclyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; R x and R y each independently represents hydrogen, R A , 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, -SF5, -Si(OR)R2, or [ka] and; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of 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 is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Variable R 3 , R 4 , R a , Q, X, X', Y, and Y' are as described and defined in WO 2010 / 077589 and US 2011 / 0319362, each of which is incorporated by reference in its entirety.

[0417] In some embodiments, R x is hydrogen. In some embodiments, R x is methanesulfonyl. In some embodiments, R x is isopropyl. In some embodiments, R x is isobutyl.

[0418] In certain embodiments, the present invention provides compounds wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-av or II-s: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-av and II-s, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3Each of Z, X, and Y is as described and defined in WO 2010 / 118309 and US 8,841,257, each of which is incorporated by reference herein in its entirety.

[0419] In certain embodiments, the present invention provides a method for treating STAT3-associated STATs, wherein the STAT is a STAT3 binding moiety, such as a STAT3-associated ... [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s'-1, II-s'-2, and II-s'-3, L and DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3 , Z, X, and Y are each independently selected from the group consisting of aryl, aryloxy, arylpropanol ... No. 8,841,257, the entireties of which are incorporated herein by reference.

[0420] In certain embodiments, the present invention provides a compound of formula II-r: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r″, L and DIM are as defined above and as described in embodiments herein; and L 1 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 1 wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X' is an optionally substituted -(CH2) x -, where one to two methylenes of X' are optionally replaced with a divalent group selected from -NR-, -N(COR)-, -N(COR)-, -N(SOR)-, -N(CONR)-, and -N(SONR)-, wherein: x is 1, 2, 3, 4, or 5; Y' is an optionally substituted -(CH2) y -where: y is 1, 2, or 3; R 3 ' is hydrogen or R A and; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Ring Z' is a divalent ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; z is 0, 1, 2, 3, or 4; and n is 0 or 1.

[0421] In certain embodiments, the present invention provides compounds of formula II-r''-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-1: X 4 ', X 5 ', and X 6 Each ' independently represents a covalent bond, -CR2-, -C(O)-, -C(S)-, -O-, -S(O)-, -S(O)2-, [ka] is a divalent moiety selected from: Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 ' is hydrogen or R A and; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D' is selected from 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic rings having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryls having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 7 ' is hydrogen, R A , 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)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, or -NRS(O)2R; p is 0, 1, 2, 3, or 4; L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~20 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, -S(O)2-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR-, -P(O)R-, or -P(O)NR2-, wherein: 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 saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, a saturated or partially unsaturated heterocyclylenyl of an 8- to 10-membered bicyclic group having 1 to 3 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; L 1 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 1 wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; X' is an optionally substituted -(CH2) x -, where one to two methylenes of X' are optionally replaced with a divalent group selected from -NR-, -N(COR)-, -N(COR)-, -N(SOR)-, -N(CONR)-, and -N(SONR)-, wherein: x is 1, 2, 3, 4, or 5; Y' is an optionally substituted -(CH2) y -where: y is 1, 2, or 3; R 3 ' is hydrogen or R A and; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Ring Z' is a divalent ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; z is 0, 1, 2, 3, or 4; and n is 0 or 1.

[0422] In some embodiments, the present invention provides a compound wherein ring D' is phenyl, p is 1, and R 7 'but, [ka] and n is 1 and Q′ is —C(O)— as shown, and the compound of formula II-r″-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-2, X 4 ', X 5 ', X 6 ', R 3 ', R 6 ', L, L 1 ', Ring M', Ring Z', X', Y', R a1 , R a2 , R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0423] In some embodiments, the present invention provides a compound wherein ring D' is phenyl, p is 1, and R 7 'but, [ka] and R 3 'but, [ka] where n is 1 and X 4 ', X 5 and Q' is -C(O)- as shown, and formula II-r''-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-3, X 6 ', R 6 ', L, L 1 ', Ring M', Ring Z', X', Y', R a1 , R a2, R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0424] In some embodiments, the present invention provides a compound wherein ring D' is phenyl, p is 1, and R 7 'but, [ka] and X' is [ka] and Y' is [ka] where n is 1 and X 4 , X 5 and Q′ is —C(O)— as shown, and formula II-r″-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-4, X 6 ', R 3 ', R 6 ', L, L 1 ', ring M', ring Z', R a1 , R a2 , R z Each of z', z, both alone and in combination, is as defined above and as described in embodiments herein.

[0425] In some embodiments, the present invention provides a compound wherein ring D' is phenyl, p is 1, and R 7 'but, [ka] and n is 1 and the ring M' is [ka] and X 4 ', X 5 and Q′ is —C(O)— as shown, and formula II-r″-5: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-5, X 4 ', X 5 ', X 6 ', R 3 ', R 6 ', L, L 1 ', ring Z', X', Y', R a1 , R a2 , R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0426] In some embodiments, the present invention provides a compound wherein ring D' is phenyl, p is 1, and R 7 'but, [ka] where n is 1 and L 1 'but, [ka] and ring Z' is phenylenyl, and X 4 , X 5 and Q′ is —C(O)— as shown, and formula II-r″-6: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-6, X 4 ', X 5 ', X 6 ', R 3 ', R 6 ', L, ring M', X', Y', R a1 , Ra2 , R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0427] In certain embodiments, the present invention provides compounds of formula II-r''-7: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r″-7, L and DIM are as defined above and as described in embodiments herein; and L 1 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 1 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; L 2 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 2 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 ' is hydrogen or R A and; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Y' is an optionally substituted -(CH2) y -where: y is 1, 2, or 3; Ring W' is an optionally substituted ring selected from 5- to 9-membered saturated or partially unsaturated heterocyclyl; Ring U' is a ring selected from phenyl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R u ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; u is 0, 1, 2, 3, or 4; Ring Z' is a bivalent ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z ' is hydrogen, R A, 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; z is 0, 1, 2, 3, or 4; and n is 0 or 1.

[0428] In certain embodiments, the present invention provides compounds of formula II-r''-8: [ka] A compound of formula II-r''-8 or a pharmaceutically acceptable salt thereof is provided, wherein: X 1 represents a covalent bond, -CR2-, -C(O)-, -C(S)-, -CR(CF3)-, -P(O)OR-, -P(O)R-, -P(O)NR2-, -S(O)-, -S(O)2-, 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 -SiR2-; R 1 is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)NR2OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, or optionally substituted C 1~4It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from: Ring B is a fused ring selected from benzo, 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, -OR, -NR2, or -SR; Each R 4 are independently hydrogen, R A , 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)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, or -NRS(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; m is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~20 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, -S(O)2-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR-, -P(O)R-, or -P(O)NR2-, wherein: 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 saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, a saturated or partially unsaturated heterocyclylenyl of an 8- to 10-membered bicyclic group having 1 to 3 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; L 1 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 1 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; L 2 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 2 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; R 3 ' is hydrogen or R A and; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Y' is an optionally substituted -(CH2) y -where: y is 1, 2, or 3; Ring W' is an optionally substituted ring selected from 5- to 9-membered saturated or partially unsaturated heterocyclyl; Ring U' is a ring selected from phenyl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R u ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; u is 0, 1, 2, 3, or 4; Ring Z' is a divalent ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; z is 0, 1, 2, 3, or 4; and n is 0 or 1.

[0429] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] and n is 1 and Y' is [ka] and ring W' is an 8-membered heterocyclyl and Q' is -C(O)- as shown, and represents a group of formula II-r''-9: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-9, R 2 , m, L, L 1 ', L 2 ', Ring M', Ring U', Ring Z', R 3 ', R a1 , R a2 , R u ', u, R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0430] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] and n is 1 and Y' is [ka] wherein ring W' is an 8-membered heterocyclyl and ring M' is [ka] and Q' is -C(O)- as shown, and is of formula II-r''-10: [ka] or a pharmaceutically acceptable salt thereof, and in formula II-r''-10, R 2 , m, L, L 1 ', L 2 ', ring U', ring Z', R 3 ', R a1 , R a2 , R u ', u, R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0431] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] and n is 1 and Y' is [ka] and ring W' is an 8-membered heterocyclyl, and L 2 'but, [ka] wherein ring U′ is phenyl and Q′ is —C(O)— as shown, and formula II-r″-11: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-11, R 2 , m, L, L 1 ', ring M', ring Z', R 3 ', R a1 , R a2 , R u ', u, R z Each of z, ', and z, both alone and in combination, is as defined above and as described in embodiments herein.

[0432] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] and n is 1 and Y' is [ka] and ring W' is an 8-membered heterocyclyl, and L 1 'but, [ka] wherein ring Z′ is cyclohexyl, z is 0, and Q′ is —C(O)— as shown, and the compound of formula II-r″-12: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-r''-12, R 2 , m, L, L 2 ', Ring M', Ring U', R 3 ', R a1 , R a2 , R u Each of ', and u, both alone and in combination, is as defined above and as described in embodiments herein.

[0433] In certain embodiments, the present invention provides a compound of formula II-s): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s″, L and DIM are as defined above and as described in embodiments herein; and L 2 ' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 2 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 ' is hydrogen or R A and; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Ring V' is an optionally substituted fused ring selected from a 6-membered aryl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; X' is an optionally substituted -(CH2) x -where: x is 0, 1, 2, or 3; Y' is an optionally substituted -(CH2) y -where: y is 0, 1, 2, or 3; Ring U' is a ring selected from phenyl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R u ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; and u is 0, 1, 2, 3, or 4.

[0434] In certain embodiments, the present invention provides compounds of formula II-s''-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s''-1: X 1 represents a covalent bond, -CR2-, -C(O)-, -C(S)-, -CR(CF3)-, -P(O)OR-, -P(O)R-, -P(O)NR2-, -S(O)-, -S(O)2-, 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 -SiR2-; R 1 is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)NR2OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)R2, -SiR3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 11-membered saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, R A, 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS (O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; Each R A independently, C 1~6 an optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from: Ring B is a fused ring selected from benzo, 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, -OR, -NR2, or -SR; Each R 4 are independently hydrogen, R A, 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)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, or -NRS(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; m is 0, 1, 2, 3 or 4; L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~20 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, -S(O)2-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR-, -P(O)R-, or -P(O)NR2-, wherein: 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 saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, a saturated or partially unsaturated heterocyclylenyl of an 8- to 10-membered bicyclic group having 1 to 3 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; L 2' denotes a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C 1~5 is a hydrocarbon chain, where L 2 ', wherein 0 to 3 methylene units are independently replaced by -O-, -NR-, -CRF-, -CF2-, -C(O)-, -S-, -S(O)-, or -S(O)2-; R 3 ' is hydrogen or R A and; Ring M' is an optionally substituted divalent ring selected from phenylenyl, naphthylenyl, a 5- to 10-membered heteroarylenyl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 11-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q' is a divalent moiety selected from -O-, -CR2-, -CF2-, -CFR-, -C(O)-, -OCR2-, and -C(S)-; R a1 and R a2 are each independently hydrogen or R A and; Ring V' is an optionally substituted fused ring selected from a 6-membered aryl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; X' is an optionally substituted -(CH2) x -where: x is 0, 1, 2, or 3; Y' is an optionally substituted -(CH2) y -where: y is 0, 1, 2, or 3; Ring U' is a ring selected from phenyl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R u ' is hydrogen, R A , 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)NROR, -CR2NRC(O)R, -CR2NRC(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, or -NRS(O)2R; and u is 0, 1, 2, 3, or 4;

[0435] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] where n is 1 and X' is [ka] wherein Y' is -CH2-, ring V' is a 6-membered aryl, and Q' is -C(O)- as shown, and formula II-s''-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s''-2, R2 , m, L, L 2 ', Ring M', Ring U', R 3 ', R a1 , R a2 , R u Each of ', and u, both alone and in combination, is as defined above and as described in embodiments herein.

[0436] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] and n is 1 and the ring M' is [ka] and X' is [ka] wherein Y' is -CH2-, ring V' is a 6-membered aryl, and Q' is -C(O)- as shown, and the compound of formula II-s''-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s''-3, R 2 , m, L, L 2 ', ring U', R 3 ', R a1 , R a2 , R u Each of ', and u, both alone and in combination, is as defined above and as described in embodiments herein.

[0437] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , X 2 , X 3 , R 1 , and ring A is [ka] where n is 1 and L 2 'but, [ka] wherein ring U' is phenyl and X' is [ka] wherein Y' is -CH2-, ring V' is a 6-membered aryl, and Q' is -C(O)- as shown, and the compound of formula II-s''-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-s''-4, R 2 , m, L, ring M', R 3 ', R a1 , R a2 , R u Each of ', and u, both alone and in combination, is as defined above and as described in embodiments herein.

[0438] X, as defined above and described herein; 4 ', X 5 ', and X 6 Each ' independently represents a covalent bond, -CR2-, -C(O)-, -C(S)-, -O-, -S(O)-, -S(O)2-, [ka] is a divalent moiety selected from

[0439] In some embodiments, X 4 In some embodiments, X ' is a covalent bond. 4 In some embodiments, X′ is —CR—. 4 is —C(O)—. In some embodiments, X 4In some embodiments, X′ is —C(S)—. 4 In some embodiments, X ' is -O-. 4 In some embodiments, X′ is —S(O)—. 4 In some embodiments, X′ is —S(O)—. 4 'teeth, [ka] In some embodiments, X 4 'teeth, [ka] In some embodiments, X 5 In some embodiments, X ' is a covalent bond. 5 In some embodiments, X′ is —CR—. 5 In some embodiments, X′ is —C(O)—. 5 In some embodiments, X′ is —C(S)—. 5 In some embodiments, X ' is -O-. 5 In some embodiments, X′ is —S(O)—. 5 In some embodiments, X′ is —S(O)—. 5 'teeth, [ka] In some embodiments, X 5 'teeth, [ka] In some embodiments, X 6 In some embodiments, X ' is a covalent bond. 6 In some embodiments, X′ is —CR—. 6 In some embodiments, X′ is —C(O)—. 6 In some embodiments, X′ is —C(S)—. 6In some embodiments, X ' is -O-. 6 In some embodiments, X′ is —S(O)—. 6 In some embodiments, X′ is —S(O)—. 6 'teeth, [ka] In some embodiments, X 6 'teeth, [ka] In some embodiments, X 6 'teeth, [ka] In some embodiments, X 6 'teeth, [ka] is.

[0440] As defined above and described herein, each R A independently, C 1~6 An optionally substituted group selected from the group consisting of aliphatic, phenyl, 4- to 7-membere...

Claims

[Claim 1] The invention described in the present specification.

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