Proteolytic agents and their uses

Abstract

To provide a method of treating diseases.SOLUTION: The invention provides compounds, compositions thereof and methods of using these for targeted degradation of proteins and for the treatment of disorders mediated by target proteins. The present invention relates to compounds and methods useful for the modulation of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and / or otherwise inhibited by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using the compositions in the treatment of various disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the targeted modulation of ubiquitination, particularly with respect to various polypeptides and other proteins that are degraded and / or otherwise inhibited by the compounds according to the invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using said compositions in the treatment of various disorders. [Background technology]

[0002] 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. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are divided into classes defined by the structural elements of their E3 functional activity.

[0003] Cereblon (CRBN) interacts with damaged DNA-binding protein 1 and forms an E3 ubiquitin ligase complex with cullin 4, which functions as a substrate receptor where proteins recognized by CRBN can be ubiquitinated and degraded by the proteasome.

[0004] Proteasome-mediated degradation of unnecessary or damaged proteins plays a crucial role in maintaining normal cellular functions (e.g., cell survival, proliferation, and growth). A new role for CRBN has been identified. Binding of immunomodulatory drugs (IMiDs) (e.g., thalidomide) to CRBN has been linked to the teratogenicity and cytotoxicity of IMiDs (including lenalidomide, which is widely used to treat patients with multiple myeloma). CRBN likely plays a key role in the binding, ubiquitination, and degradation of factors involved in maintaining myeloma cell function. These new findings regarding the role of CRBN in IMiD action have stimulated intensive research into downstream factors of CRBN involved in maintaining normal cellular function (Chang and Stewart Int J Biochem Mol Biol. 2011;2(3):287-294).

[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) specific protein (b) diseases resulting from loss of function, which results in stabilizing quality, 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 multiple myeloma. However, non-specific effects and the inability to target and regulate specific classes of proteins (e.g., transcription factors) together remain obstacles to the development of effective anti-cancer drugs. Therefore, small molecule therapeutic agents that specifically affect or enhance cereblon substrates and are simultaneously "tunable" so that a wide range of protein classes can be specifically targeted and regulated would be highly useful as therapeutic agents. Therefore, there remains a need to find bifunctional compounds that are useful as therapeutic proteolytic agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Chang and Stewart Int J Biochem Mol Biol.2011;2(3):287-294 [Non-patent document 2] Crews C,Chemistry & Biology,2010,17(6):551-555 [Non-patent document 3] 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 targeted 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 various polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, compatible with the degradation / inhibition of target polypeptides from virtually any protein class or family. Furthermore, the present application provides methods for using an effective amount of the compounds described herein to treat or alleviate disease conditions, such as cancer, e.g., multiple myeloma.

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

[0011] The present application also provides a method for producing a compound having the following structure: [ka] and a bifunctional compound having the formula: TBM is a target binding moiety capable of binding to the protein(s) to be targeted; L is a bivalent moiety connecting the TBM to the UBM; and A UBM is a ubiquitin-binding moiety that can bind to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon).

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

[0013] Other compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found to be effective for the targeted modulation of ubiquitination. Such compounds have the general formula I): [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0014] Other compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found to be effective for the targeted modulation of ubiquitination. Such compounds have the general formula II-A: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0015] Other compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found to be effective for the targeted modulation of ubiquitination. Such compounds have the general formula II"-A: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0016] Other compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found to be effective for the targeted modulation of ubiquitination. Such compounds have the general formula II-B: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0017] Other compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found to be effective for the targeted modulation of ubiquitination. Such compounds have the general formula II"-B: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0018] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions, including those described herein.

[0019] The compounds provided by the present invention are also useful for the study of CRBN and targeted proteins in biological and pathological phenomena; the study of CRBN and targeted proteins as they occur in body tissues; and the comparative evaluation, in vitro or in vivo, of new CRBN or targeted proteins or other regulators of CRBN or targeted proteins. DETAILED DESCRIPTION OF THE INVENTION

[0020] 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 for modulating targeted ubiquitination.

[0021] As defined herein, the terms "binding agent," "modulator," and "ligand" are used interchangeably and describe compounds that bind to, modulate, or are ligands for CRBN or a targeted protein.

[0022] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: 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] is a bicyclic or tricyclic ring selected from Ring B 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; 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 Independently from aliphatic, phenyl, nitrogen, oxygen, and sulfur an optionally substituted group selected from 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; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0023] In certain embodiments, the present invention provides a compound of formula I': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I': 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 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] is a bicyclic or tricyclic ring selected from Ring B 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; 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)N R2, -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 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 -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 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, 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.

[0024] In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I″: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; Ring A is [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; R 3represents hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R) selected from 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; Each R 4 are independently hydrogen, deuterium, -R 6 , halogen, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; R 5 is hydrogen, deuterium, optionally substituted C 1~4 Aliphatic, or -C N; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; 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 selected from -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each R is independently hydrogen, deuterium, 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, form a four-membered ring system having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Forms a 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0025] [ka] is depicted on ring B, [ka] It is envisioned, and will be understood by one of ordinary skill in the art, that the point of attachment of may be on ring A and may be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. [ka] But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and [ka] But R 4 group or R 5 Replaces the base. [ka] But R 3 If attached to a carbon atom that is bonded to R 3does not exist, and [ka] But R 3 By way of example and for clarity, [ka] When is attached to ring B, ring A is [ka] and; [ka] When is bonded to ring A, ring A is [ka] and; [ka] But R 4 If the ring is attached to a nitrogen atom that is attached to [ka] and; [ka] But R 5 If the ring is attached to a nitrogen atom that is attached to [ka] and [ka] But R 3 If ring A is attached to a carbon atom that is attached to [ka] is.

[0026] -(R 2 ) n When the attachment point of -(R 2 ) n It is contemplated, 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 boron, carbon, nitrogen, or silicon 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 Replaces the base. -R 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 Replaces the base.

[0027] In certain embodiments, the present invention provides a compound of formula II-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-A: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4 , 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 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, 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.

[0028] In certain embodiments, the present invention provides a compound of formula II'-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II'-A: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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. ; Each R 3 are independently hydrogen, -R 4 , 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0029] In certain embodiments, the present invention provides a compound of formula II''-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in II″-A: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Each R 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) selected from 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; Each R 4 independently, C1~6 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 boron, nitrogen, oxygen, silicon, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, deuterium, optionally substituted C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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 a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0030] In certain embodiments, the present invention provides compounds of formula II-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-B: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4 , 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0031] In certain embodiments, the present invention provides a compound of formula II'-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II'-B: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4, 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0032] In certain embodiments, the present invention provides a compound of formula II''-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II″-B: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 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) selected from 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; Each R 4 independently, C 1~6 an optionally substituted group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, or sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, deuterium, optionally substituted C 1~4 Aliphatic, or -C N; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each R is independently hydrogen, deuterium, 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, 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.

[0033] [ka] is depicted on ring A, [ka] It is contemplated, and one of ordinary skill in the art will appreciate, that the point of attachment of can be at any available carbon or nitrogen atom on ring A. [ka] But R 3 or R 5 If bonded to a nitrogen atom bonded to R 3 or R 5 does not exist, and [ka] But R 3 group or R 5 Replaces the base.

[0034] In certain embodiments, the present invention provides compounds of formula III-A, III-B, or III-C: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula III-A, III-B, and III-C, L and TBM 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 , W2 , X and n are each independently selected from the group consisting of WO 2004 / 022994, which is incorporated herein by reference in its entirety. As defined in 2017 / 197051, and [ka] is R 1 , R 1 and R 2 or R as defined in WO 2017 / 197051. 12 R in the binding site of 17 is bound to, resulting in [ka] But R 12 It replaces the substituent.

[0035] 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 used. "Organic Chemistry," Thomas Sorrell, University 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.

[0036] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0037] 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:

[0038] 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.

[0039] 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.

[0040] 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)).

[0041] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] The term "cyclopropyl" refers to a divalent cyclopropyl group.

[0046] The term "halogen" means F, Cl, Br, or I.

[0047] 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.

[0048] 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, wherein the alkyl and heteroaryl portions independently are optionally substituted. are substituted accordingly.

[0049] 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).

[0050] 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, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 hydrogen , 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.

[0056] 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)0~1 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.

[0057] 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.

[0058] 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.

[0059] 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, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid), or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, and the like. Lauryl phosphate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate salts, such as hydroxybenzoates, ...

[0060] 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.

[0061] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14 Compounds having the present invention in which C is replaced with enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools according to the present invention, as probes in biological assays, or as therapeutic agents. In certain embodiments, provided compounds can be substituted with one or more deuterium atoms.

[0062] As used herein, the term "binding agent" or "inhibitor" is defined as a compound that binds CRBN and binds or inhibits a targeted 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.

[0063] 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 attached to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing a carbonate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name a few. It is understood that such moieties can be directly attached to a provided compound or attached via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties are The moiety can be attached by click chemistry. In some embodiments, such moieties can be attached by 1,3-cycloaddition of azide with alkyne, optionally in the presence of copper catalyst. Methods using click chemistry are known in the art, including those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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 tags 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 Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516, 5,660,8192, 5,660,8193, 5,660,8194, 5,660,8195, 5,660,8196, 5,660,8197, 5,660,8198, 5,660,819 ...

[0004] Mass tags are described in US Pat. Nos. 5,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides 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.

[0068] The terms "measurable affinity" and "measurably modulate," as used herein, refer to a measurable change in CRBN activity between a sample containing a compound of the invention or composition thereof and CRBN and an equivalent sample containing CRBN without the compound or composition thereof present.

[0069] 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: 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] is a bicyclic or tricyclic ring selected from Ring B 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; 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 is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein the 0 to 6 methylene units of L are independently -Cy-, - O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0070] As noted above, in certain embodiments, the present invention provides a compound of formula I': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I': 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 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] is a bicyclic or tricyclic ring selected from Ring B 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; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)R; 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 is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0071] In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I″: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)NR2; Ring A is [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; R 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) selected from 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; Each R 4 are independently hydrogen, deuterium, -R 6, halogen, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; R 5 is hydrogen, deuterium, optionally substituted C 1~4 Aliphatic, or -C N; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -C(H)(CF3)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, form a four-membered ring system having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Forms a 7-membered saturated, partially unsaturated, or heteroaryl ring.

[0072] As noted above, in certain embodiments, the present invention provides compounds of formula II-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-A: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4, 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0073] As noted above, in certain embodiments, the present invention provides compounds of formula II'-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II'-A: 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 A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4, 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0074] In certain embodiments, the present invention provides a compound of formula II''-A: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II″-A: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, deuterium, -R 4 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; Each R 3 is hydrogen, deuterium, -R 4 , 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, selected from -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; Each R 4independently, C 1~6 an optionally substituted group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, or sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, deuterium, optionally substituted C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; 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 A and ring B is [ka] It is bound to; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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 a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0075] As noted above, in certain embodiments, the present invention provides compounds of formula II-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-B: 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 A is [ka] [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4 , 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated an optionally substituted bivalent ring selected from 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 7-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0076] As noted above, in certain embodiments, the present invention provides compounds of formula II'-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II'-B: 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 A is [ka] [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, -R 4 , 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 B 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; Each R 3 are independently hydrogen, -R 4 , 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; Each R 4 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -N(R)-, -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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, 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.

[0077] In certain embodiments, the present invention provides a compound of formula II''-B: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II″-B: X 1 is a covalent bond, -C(R)2-, -C(O)-, -C(S)-, -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 -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, or -O-; X 4 is a divalent moiety selected from a covalent bond or -C(R)2-; [ka] is a single or double bond; R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 aliphatic or: R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring A is [ka] a monocyclic or bicyclic ring selected from: Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2; Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; Each R 3 is hydrogen, deuterium, -R 4 , 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, selected from -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; Each R 4 independently, C 1~6an optionally substituted group selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, or sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 is hydrogen, deuterium, optionally substituted C 1~4 aliphatic, or -CN; L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, 6- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. or a partially unsaturated spiroheterocyclylenyl, a 5- to 12-membered bridged or unbridged, bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; TBM is the target binding moiety; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each R is independently hydrogen, deuterium, 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, 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.

[0078] As defined above and described herein, X 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

[0079] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 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.

[0080] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0081] As defined above and described herein, X 2 is a carbon atom or a silicon atom.

[0082] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.

[0083] In some embodiments, X 2 is selected from those illustrated in Table 1 below.

[0084] As defined above and described herein, X 3 is a divalent moiety selected from -CH2-, -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, -CH(R)-, or -O-.

[0085] 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 -O-.

[0086] In some embodiments, X 3 is selected from those illustrated in Table 1 below.

[0087] As defined above and described herein, X 4 is a divalent moiety selected from a covalent bond, —CH2—, or —C(R)2—.

[0088] In some embodiments, X 4 is a covalent bond. In some embodiments, X 4 is -CH2-. In some embodiments, X 4 is -C(R)2-.

[0089] In some embodiments, X 4 is selected from those illustrated in Table 1 below.

[0090] As defined above and described herein, R 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 Aliphatic or R 1 and X 1 or X 4 together with the atoms therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1is -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 therebetween to form a 5- to 7-membered saturated, partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0093] As defined above and described herein, each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

[0094] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is deuterium. In some embodiments, R 2 Ha-R 6 In some embodiments, R 2 is halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is —NO. In some embodiments, R 2 In some embodiments, R 2 is —Si(OH)R. In some embodiments, R 2 is —Si(OH)(R). In some embodiments, R 2 In some embodiments, R 2 is -NR2. In some embodiments, R 2 is —Si(R). In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 Ha-S (O)NR. In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is —C(O)R. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2is —C(O)NR. In some embodiments, R 2 is —C(O)N(R)OR. In some embodiments, R 2 is -OC(O)R. In some embodiments, R 2 is —OC(O)NR. In some embodiments, R 2 is —N(R)C(O)OR. In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is —N(R)C(O)NR. In some embodiments, R 2 is —N(R)S(O)R. In some embodiments, R 2 is -P(O)(OR). In some embodiments, R 2 is -P(O)(NR2)OR. In some embodiments, R 2 is -P(O)(NR2)2.

[0095] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0096] As defined above and described herein, ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from:

[0097] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0098] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0099] In some embodiments, A is selected from those depicted in Table 1 below.

[0100] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl containing 0 to 3 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0101] In some embodiments, ring B is a 6-membered aryl containing 0 to 3 nitrogen atoms. In some embodiments, ring B is a 5- to 7-membered partially saturated carbocyclyl. In some embodiments, ring B is a 5- to 7-membered partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring B is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0102] 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.

[0103] 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, each ring B is [ka] is.

[0104] 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.

[0105] 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] .

[0106] 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.

[0107] In some embodiments, ring B is [ka] [ka] is selected from.

[0108] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0109] As defined above and described herein, [ka] is a single or double bond.

[0110] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

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

[0112] As defined above and described herein, R 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.

[0113] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 In some embodiments, R 3 is -NR2. In some embodiments, R 3 In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is —C(O)R. In R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3is —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, R 3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3 is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R 3 is -Si(R)3.

[0114] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0115] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0116] 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.

[0117] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 Ha-R 6 In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is —NO. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is -NR2. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)NR. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is —C(O)R. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —C(O)NR. In some embodiments, R 4 is —C(O)N(R)OR. In some embodiments, R4 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.

[0118] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0119] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0120] As defined above and described herein, R 5 is hydrogen, deuterium, optionally substituted C 1~4 It is aliphatic, or -CN.

[0121] 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.

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

[0123] As defined above and described herein, each R 6 independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0124] In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or 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.

[0125] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0126] As defined above and described herein, 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 selected from -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] has been replaced by

[0127] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by

[0128] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0129] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0130] In some embodiments, L is selected from those depicted in Table 1 below.

[0131] As defined above and described herein, each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 10-membered saturated or partially unsaturated heterocyclyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.

[0132] In some embodiments, -Cy- is an optionally substituted bivalent ring selected from phenylenyl. In some embodiments, -Cy- is an optionally substituted 8- to 10-membered bicyclic arylenyl. In some embodiments, -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 5- to 12-membered, bridged or unbridged, bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 4- to 10-membered saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.

[0133] In some embodiments, -Cy- is [ka] is.

[0134] In some embodiments, -Cy- is selected from those depicted in Table 1 below.

[0135] As defined above and described herein, a TBM is a target binding moiety.

[0136] In some embodiments, the TBM is a target binding moiety.

[0137] In some embodiments, the TBM binds to a protein selected from those listed in paragraph

[0181] .

[0138] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein the drug is: [ka] at any modifiable carbon, oxygen, sulfur or nitrogen atom.

[0139] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein the drug is: [ka] at any modifiable carbon, oxygen, sulfur or nitrogen atom.

[0140] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein the drug is: [ka] at any modifiable carbon, oxygen, sulfur or nitrogen atom.

[0141] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein the drug is: [ka] at any modifiable carbon, oxygen, sulfur or nitrogen atom.

[0142] In some embodiments, the TBM [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] In some embodiments, the TBM is [ka] is.

[0143] In some embodiments, the TBM is selected from those depicted in Table 1 below.

[0144] As defined above and described herein, m is 0, 1, 2, 3, or 4.

[0145] 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.

[0146] In some embodiments, m is selected from those depicted in Table 1 below.

[0147] As defined above and described herein, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0148] 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. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0149] In some embodiments, n is selected from those depicted in Table 1 below.

[0150] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group, and the optionally substituted group is C 1~6 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; or two R groups on the same nitrogen, together with the atoms between them, may be selected from boron, silicon, and sulfur in addition to the nitrogen. Forms a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, silicon, and sulfur.

[0151] 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.

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

[0153] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 , R 1 , R 5 , R, -Cy-, and TBM are as described above for Formula I and herein, and Ring A, Ring B, R 2 , R 3 , R 4 , L, m, n, p, and q are as described below for Formula II-A and II-B and herein.

[0154] As defined above and described herein, ring A is [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0155] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0156] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0157] In some embodiments, A is [ka] is a monocyclic or bicyclic ring selected from:

[0158] In some embodiments, A is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0159] In some embodiments, A is [ka] is selected from.

[0160] In some embodiments, A is [ka] is selected from.

[0161] In some embodiments, A is selected from those depicted in Table 1 below.

[0162] As defined above and described herein, each R 2 are independently hydrogen, deuterium, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, -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, -N(R)S(O)2NR2, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

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

[0164] In some embodiments, R 2 is methyl.

[0165] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0166] As defined above and described herein, Ring B is selected from a 6-membered aryl containing 0 to 3 nitrogen atoms or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0167] In some embodiments, Ring B is a 6-membered aryl containing 0-3 nitrogen atoms, hi some embodiments, Ring B is a 5-membered heteroaryl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0168] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0169] As defined above and described herein, each R 3 are independently 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.

[0170] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 In some embodiments, R 3 is -NR2. In some embodiments, R 3 In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is —C(O)R. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3 is —C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, Te, 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 3is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R 3 is —N(R)P(O)(OR)NR. In some embodiments, R 3 is -P(O)(OR). In some embodiments, R 3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3 is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R 3 is -Si(R)3.

[0171] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0172] As defined above and described herein, each R 4 independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0173] In some embodiments, R 4 is replaced by C 1~6 In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4is 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, or sulfur. In some embodiments, R 4 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0174] In some embodiments, R 4 is methyl.

[0175] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0176] As defined above and described herein, L is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C 1~50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by

[0177] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent, saturated or unsaturated, straight or branched chain C 1~50a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently selected from -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] has been replaced by

[0178] In some embodiments, L is selected from those depicted in Table 1 below.

[0179] As defined above and described herein, m is 0, 1, or 2.

[0180] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0181] In some embodiments, m is selected from those depicted in Table 1 below.

[0182] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0183] 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.

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

[0185] As defined above and described herein, p is 0 or 1, where when p is 0, the bond connecting ring A and ring B is [ka] is bonded to.

[0186] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 0 and the bond connecting ring A and ring B is [ka] is bonded to.

[0187] In some embodiments, p is selected from those depicted in Table 1 below.

[0188] As defined above and described herein, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0189] 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. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8. In some embodiments, q is 9. In some embodiments, q is 10.

[0190] In some embodiments, q is selected from those depicted in Table 1 below.

[0191] In a preferred aspect of the present invention, the TBM group is a group that binds to a target protein. Targets for the TBM group are numerous and are selected from proteins that are expressed in cells, at least a portion of whose sequence is found within the cell, and that can bind to the TBM group. The term "protein" encompasses oligopeptide and polypeptide sequences of sufficient length to be capable of binding to a TBM group according to the present invention. As described herein, any protein in a eukaryotic system is a target for ubiquitination mediated by the compounds according to the present invention.

[0192] TBM groups according to the present invention include, for example, any moiety that specifically binds to a protein (binds to a target protein), and include the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. The compositions below exemplify some of the members of these nine classes of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding moieties are attached, possibly via a linker, to a ubiquitin ligase binding moiety for the purpose of presenting the target protein (to which the protein target moiety is attached) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0193] Any protein that can bind to a target binding moiety or TBM group and be acted upon or degraded by a ubiquitin ligase is a target protein according to the present invention. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integrated function of cells (including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, protein degradation, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, proteins having a response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity). Proteins of interest can include proteins from eukaryotic and prokaryotic cells, including humans (as targets for drug therapy), other animals (including domesticated animals), microorganisms (for the determination of targets for antibiotics and other antimicrobial agents and plants), and even viruses, among many others.

[0194] A TBM (or target binding moiety) is a small molecule that can bind to or binds to a target protein of interest.

[0195] Some embodiments of the present application relate to TBMs, including, but not limited to, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, compounds targeting the cytosolic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0196] In some embodiments, the TBM comprises: [ka] [ka] wherein R is a BRD ligand selected from: [ka] [ka] Represents a bond to

[0197] In some embodiments, the TBM comprises: [ka] [ka] wherein R is a CREBBP ligand selected from: [ka] [ka] X is N or C; and n is 0-8.

[0198] In some embodiments, the TBM comprises: [ka] wherein R is a SMARCA4 / PB1 / SMARCA2 ligand selected from: [ka] [ka] X is N or C; and n is 0-8.

[0199] In some embodiments, the TBM comprises: [ka] wherein R is a TRIM24 / BRPF1 ligand selected from: [ka] [ka] and n is 0 to 8.

[0200] In some embodiments, the TBM comprises: [ka] [ka] wherein R is a glucocorticoid receptor ligand selected from: [ka] [ka] Represents a bond to

[0201] In some embodiments, the TBM comprises: [ka] [ka] wherein R is an estrogen / androgen receptor ligand selected from: [ka] [ka] Represents a bond to

[0202] In some embodiments, the TBM comprises: [ka] wherein R is a DOT1L ligand selected from: [ka] X is N or C; and n is 0-8.

[0203] In some embodiments, the TBM comprises: [ka] wherein R is a BRAF ligand selected from: [ka] [ka] Represents a bond to

[0204] In some embodiments, the TBM comprises: [ka] [ka] wherein R is a Ras ligand selected from: [ka] Represents a bond to

[0205] In some embodiments, the TBM comprises: [ka] wherein R is a RasG12C ligand selected from: [ka] [ka] Represents a bond to

[0206] In some embodiments, the TBM comprises: [ka] wherein R is a Her3 ligand selected from: [ka] and R' is -CH2CH3 or -CH=CH2.

[0207] In some embodiments, the TBM comprises: [ka] wherein R is a Bcl-2 / Bcl-XL ligand selected from: [ka] [ka] Represents a bond to

[0208] In some embodiments, the TBM comprises: [ka] wherein R is an HDAC ligand selected from: [ka] [ka] Represents a bond to

[0209] In some embodiments, the TBM comprises: [ka] wherein R is a PPAR-γ ligand selected from: [ka] [ka] Represents a bond to

[0210] In some embodiments, the TBM comprises: [ka] is selected from, where [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0211] In some embodiments, the TBM is selected from the group consisting of the following non-limiting examples: [ka] [ka] [ka] Abl, KRAS, SHP2, cRAF, MerTK or PRMT5 ligand selected from [ka] [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0212] In some embodiments, the TBM moiety is selected from the PTM moieties described in WO 2016 / 197032, the entire contents of which are incorporated herein by reference. In some embodiments, the TBM moiety is selected from the inhibitors as described in paragraphs

[0116] to

[0173] of WO 2016 / 197032, where the description of the "linker" moiety in WO 2016 / 197032 corresponds to the -L- group as defined and described herein.

[0213] In some embodiments, the TBM comprises: [ka] [ka] wherein the KRAS ligand is selected from [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0214] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0215] In some embodiments, the method employs a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the present invention provides a compound of formula I, wherein the compound is not any of the compounds depicted in Table A-1 below.

[0217] [Table A1]

[0218] In some embodiments, the invention provides a compound of formula II-A, wherein the compound is not any of the compounds depicted in Table A-2 below.

[0219] [Table A2-1] [Table A2-2] [Table A2-3] [Table A2-4]

[0220] In some embodiments, the TBM is one of the compounds in Table 2 below, wherein [ka] [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0221] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Table 2-55 Table 2-56 Table 2-57 Table 2-58 Table 2-59 Table 2-60 Table 2-61 Table 2-62 Table 2-63 Table 2-64 Table 2-65 Table 2-66 Table 2-67 Table 2-68 Table 2-69 Table 2-70 Table 2-71 Table 2-72 Table 2-73 Table 2-74 Table 2-75 Table 2-76 Table 2-77 Table 2-78 Table 2-79 Table 2-80 Table 2-81 Table 2-82 Table 2-83 Table 2-84 Table 2-85 Table 2-86 Table 2-87 Table 2-88 Table 2-89 Table 2-90 Table 2-91 Table 2-92 Table 2-93 Table 2-94 Table 2-95 Table 2-96 Table 2-97 Table 2-98 Table 2-99 Table 2-100 Table 2-101 Table 2-102

Table 2-103

Table 2-130

Table 2-139

[0222] 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of the compound in the composition of the present invention is such that it is effective to measurably bind CRBN or its mutant and the target protein in a biological sample or in a patient.In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition.In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0223] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0224] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, and portions of saturated vegetable fatty acids. These include: a mixture of glycerides, water, electrolytes such as salt or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0225] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, the compound of this invention or an inhibitory active metabolite or residue thereof.

[0226] As used herein, the term "active metabolite or residue thereof" means that the metabolite or residue thereof is also a binding agent of CRBN or a variant thereof, or a targeted protein or a variant thereof.

[0227] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0228] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated form, are useful for preparing injectable substances, as are natural pharmaceutically acceptable oils such as olive oil or castor oil.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions.Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0229] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0230] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These are solid at room temperature but liquid at rectal temperature, but These can be prepared by mixing the drug with a suitable non-irritating excipient that will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0231] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0232] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0233] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0234] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0235] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0236] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0237] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg of compound per kg of body weight per day can be administered to a patient receiving these compositions.

[0238] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition may vary depending on the amount of the compound in the composition. It will also vary depending on the particular compounds in the product. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0239] Described herein are compositions and methods related to the surprising and unexpected discovery that an E3 ubiquitin ligase protein (e.g., cereblon) ubiquitinates a target protein once the two proteins are brought into close proximity by a bifunctional or chimeric construct that links the E3 ubiquitin ligase protein and the target protein. Accordingly, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("UBM") linked to a protein target binding moiety ("TBM"), resulting in ubiquitination of a selected target protein, which leads to degradation of the target protein by the proteasome.

[0240] The compounds and compositions described herein are generally useful for targeted modulation of ubiquitination, particularly with respect to various polypeptides and other proteins that are to be degraded and / or otherwise inhibited. In some embodiments, proteins inhibited by the compounds and methods of the present invention include those listed in paragraph

[0181] .

[0241] The compounds and compositions described herein exhibit a wide range of pharmacological activities, consistent with targeted degradation / inhibition of polypeptides.

[0242] Therefore, compounds that bind to CRBN, particularly those that have high selectivity over E3 ligases, would be beneficial. Such compounds would deliver pharmacological responses that favorably treat one or more of the conditions described herein without the side effects associated with inhibiting E3 ligases.

[0243] Although CRBN-binding agents are known in the art, there remains a need to provide novel binding agents with more effective or advantageous pharmaceutically relevant properties, such as compounds with increased activity, high selectivity over other E3 ligases, and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the present invention provides binding agents of CRBN that exhibit high selectivity over other E3 ligases.

[0244] The activity of the compounds utilized in this invention as inhibitors of CRBN or its mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the activity or subsequent functional consequences of activated CRBN or its mutants. An alternative in vitro assay quantifies the ability of a compound to bind to CRBN. Binding can be measured by radiolabeling the compound prior to binding, isolating the compound / CRBN complex, and determining the amount of bound radiolabel. Alternatively, compound binding can be determined by performing a competition experiment in which a novel compound is incubated with CRBN bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying CRBN binding agents include, for example, those described and disclosed in Boichenko et al. J. Med. Chem. (2016) 59, 770-774 and Iconomou and Saunders Biochemical Journal (2016) 473, 4083-4101, each of which is incorporated herein by reference in its entirety. Detailed conditions for assaying compounds utilized as binders of CRBN or its variants in this invention are described in the Examples below.

[0245] The term "ubiquitin ligase" refers to a specific ubiquitin ligase that targets substrate proteins for degradation. It refers to a family of proteins that facilitate the transfer of ubiquitin to substrate proteins. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin-conjugating enzyme, causes ubiquitin to be attached to the lysine on the target protein, and then targets the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin-conjugating enzyme, is responsible for the transfer of ubiquitin to the targeted protein. Generally, ubiquitin ligase is involved in polyubiquitination, whereby a second ubiquitin binds to the first ubiquitin, a third ubiquitin binds to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead their cellular location or function can be altered, for example, by binding to other proteins with domains capable of binding ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by a single E3 to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin that is recognized by the proteasome.

[0246] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0247] The present disclosure provides therapeutic compositions described herein for causing degradation of a protein of interest to treat or alleviate a disease (e.g., cancer). In certain further embodiments, the disease is multiple myeloma. Accordingly, in another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, the compound comprising a UBM and a TBM linked via a linker moiety, e.g., as described elsewhere herein, wherein the UBM is bound to the TBM, and the UBM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase, such as cereblon), and the TBM recognizes the target protein, such that, when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thereby resulting in degradation of the target protein and / or inhibition of its effect and control of protein levels. The control of protein levels provided by the present invention provides for the treatment of a disease state or condition regulated via a target protein by reducing the level of the target protein intracellularly, e.g., in a patient's cells. In certain embodiments, the method includes administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0248] In a further embodiment, the present disclosure provides a method for treating or alleviating a disease, disorder, or symptom thereof in a subject or patient, the method comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or comprises administering a composition containing these combinations, wherein the composition is effective to treat or alleviate the disease or disorder or symptoms thereof in the subject.

[0249] In another aspect, the present specification provides methods for identifying the effect of degradation of a protein of interest in a biological system using compounds according to the present invention.

[0250] In another embodiment, the present invention relates to a method of treating a human patient in need of a disease state or condition regulated through a protein, wherein degradation of the protein causes a therapeutic effect in the patient, comprising administering to a patient in need thereof an effective amount of a compound according to the present invention, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial or other harmful agent (e.g., a virus, bacteria, fungus, protozoan, or other pathogen), or may be a disease state caused by overexpression of a protein that results in the disease state and / or condition.

[0251] Conditions which may be treated using the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, cystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle-cell disease, Tay-Sachs disease, Turner syndrome.

[0252] Further disease states or conditions which may be treated by the compounds according to the invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar depression, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, vasculitis.

[0253] Still further disease states or conditions that may be treated by the compounds according to the invention include, among others, aceruloplasminemia, type II achondroplasia, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha 1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis Alström syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen resistance syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome, multiple arthrochalasia type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, type II neurofibromatosis, Behre-Stevenson gyriform scalp syndrome, Mediterranean fever, familial, Benjamin amin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (type II neurofibromatosis), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, and Brittle bone disease. bone disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taebi syndrome), Bronze diabetes mellitus / Bronzed cirrhosis (hemochromatosis), Spinal-bulbar muscular atrophy (Kennedy disease), Buerger-Grütz syndrome (lipoprotein lipase deficiency), Chronic Granulomatous Disease (CGD), Ankle Dysplasia, Biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cricus cricus, Congenital Absence of the Vas Deferens (CAVD), Caylor Cardio-Facial Syndrome (CBAVD), Congenital Hematopoietic Porphyria (CEP), Cystic Fibrosis, Congenital Thyroid Dysfunction, Achondroplasia Syndrome (achondroplasia), Achondroplasia with Sensorineural Hearing Loss, Lesch-Nyhan Syndrome , Galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (Familial adenomatous polyposis), Congenital erythropoietic porphyria, Congenital heart disease, Methemoglobinemia / Congenital methemoglobinemia, Achondroplasia, X-linked sideroblastic anemia, Connective tissue disease, Conotruncal dysfacies syndrome, Cooley anemia (β-thalassemia), Copper storage disease (Wilson's disease), Copper transport disorder (Menkes disease), Hereditary coproporphyria, Cowden syndrome, Craniofacial dysostosis dysarthrosis (Curzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophies, Duchenne and Becker types (DBMD), Usher syndrome, degenerative neurological diseases (including de Grouchy syndrome and Déjerine-Sottas syndrome), developmental disorders, distal spinal muscular atrophy,Type V, androgen resistance syndrome, diffuse globoid sclerosis (Clavier's disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen resistance syndrome, Down's syndrome, dwarfism, erythropoietic protoporphyria (erythrocytic 5-aminolevulinic acid synthetase deficiency), erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure sensitive neuropathy neuropathy), primary pulmonary hypertension (PPH), fibrocystic pancreatic disease, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Glenn-Blood-Strandberry syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders (including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, and Jackson-Weiss syndrome), kidney disease (including hyperoxaluria), Klinefelter syndrome, Kniest dysplasia, patchy dementia, Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Kniest dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Menke syndrome, multiple neurofibromas, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, multiple fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degeneration Dementia, Prion Disease, Progeria (Hutchinson-Gilford Progeria Syndrome), Progressive Chorea, Chronic Hereditary (Huntington's Disease), Progressive Muscle Atrophy, Spinal Muscular Atrophy, Propionic Aciduria, Protoporphyria, Proximal Myotonic Dystrophy, Pulmonary Arterial Hypertension, PXE (Pseudoxanthoma Elasticum), Rb (Retinoblastoma), Recklinghausen's Disease (Neurofibromatosis Type I), Recurrent Multiple Sesitis, Retinopathy, Ret Syndrome, Rett Syndrome, RFALS Type 3, Rickel Syndrome, Riley-Day Syndrome, Lucy-Levi Syndrome, Severe Achondroplasia with Developmental Retardation and Acanthosis Nigricans (SADDAN), Li-Fraumeni Syndrome, Sarcoma, Breast, Leukemia, and Adrenal (SBLA) Syndrome, Tuberous Sclerosis (Tuberous Sclerosis) sclerosis)), SDAT, congenital SED (congenital spondylo-epiphyseal dysplasia), SED Strudwick (spondylo-epiphyseal dysplasia, Strudwick type), SEDc (congenital spondylo-epiphyseal dysplasia) SEMD, Strudwick type (spondylo-epiphyseal dysplasia),Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Ty-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen resistance syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, sausage neuropathy (hereditary neuropathy with predisposition to pressure palsies), Treacher-Collins syndrome, XXX syndrome (Triplo X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Vrolik disease These include Waardenburg syndrome, Warburg-Sjo-Fledelius syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weisenbacher-Zweymüller syndrome, and xeroderma pigmentosum.

[0254] The term "neoplasia" or "cancer" is used throughout this specification to refer to a pathological process that results in the formation and growth of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation, often faster than normal, and that continue to grow even after the stimulus that initiated this new growth has ceased. Malignant neoplasms exhibit partial or complete loss of structural organization and functional coordination with normal tissue, and most tend to invade surrounding tissues, metastasize to several sites, and recur after attempted elimination, causing the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous conditions and encompasses or includes the pathological processes associated with malignant hematogenous, eosinophilic, and solid tumors. Exemplary cancers that may be treated by the compounds of the present invention, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; bladder, bowel, breast, cervix, colon, esophagus, head, kidney, Cancer of the kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas (Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma) as), neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma); intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that can be treated using the compounds according to the invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0255] In some embodiments, the present invention provides methods for treating one or more disorders, wherein the disorders are selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the compounds of the present invention are selected from the group consisting of A1BG, A1CF, A2M, A2ML1, A3GALT2 ,A4GALT, A4GNT, AAAS, AACS, AADAC, AADACL2, AADACL3, AADACL4, AADAT, AAED1, AAGAB, AAK1, AAMDC, AAMP, AANAT, AAR2, AARD, AARS, AARS2, AARSD1, AASDH, AASDHPPT, AASS, AATF, AATK, AATK-AS1, ABAT, ABCA1, ABCA10, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCA6, ABCA7, ABCA8, ABCA9, ABCB1, ABCB10, ABCB11, ABCB4, ABCB5, ABC B6、ABCB7、ABCB8、ABCB9、ABCC1、ABCC10、ABCC11、ABCC12、ABCC2、ABCC3、ABCC4、ABCC5、ABCC6、ABCC8、ABCC9、ABCD1、ABCD2、ABCD3、ABCD4、ABCE1、ABCF1、ABCF2、ABCF3 ABCG1、ABCG2、ABCG4、ABCG5、ABCG8、ABHD1、ABHD10、ABHD11、ABHD12、ABHD12B、ABHD13、ABHD14A、ABHD14A-ACY1、ABHD14B、ABHD15、ABHD16A、ABHD16B、ABHD17A、ABHD17B 、ABHD17C、ABHD18、ABHD2、ABHD3、ABHD4、ABHD5、ABHD6、ABHD8、ABI1、ABI2、ABI3、ABI3BP、ABL1、ABL2、ABLIM1、ABLIM2、ABLIM3、ABO、ABR、ABRA、ABRACL、ABRAXAS1、ABRAXAS2、ABT1、ABTB1、ABTB2、AC001226.2、AC002094.3、AC002115.2、AC002310.4、AC002310.5、AC002429.2、AC002985.1、AC002996.1、AC003002.1、AC003002.2、AC003002.3、AC003002.4、AC003005.1、AC003006.1、AC003688.1、AC004076.1、AC004080.3、AC004223.3、AC004233.2、AC004556.1、AC004691.2、AC004706.4、AC004754.1、AC004805.1、AC004832.3、AC004922.1、AC004997.1、AC005020.2、AC005041.1、AC005154.6、AC005258.1、AC005324.3、AC005324.4、AC005520.1、AC005551.1、AC005670.2、AC005697.1、AC005702.2、AC005726.2、AC005779.2、AC005832.4、AC005833.1、AC005833.3、AC005837.2、AC005841.2、AC005885.1、AC005943.1、AC006030.1、AC006254.1、AC006269.1、AC006449.4、AC006486.1、AC006538.2、AC006978.2、AC007040.2、AC007192.1、AC007240.1、AC007325.1、AC007325.2、AC007325.4、AC007326.4、AC007375.2、AC007383.6、AC007537.5、AC007731.5、AC007906.2、AC007998.2、AC008073.3、AC008162.2、AC008393.2、AC008403.1、AC008481.3、AC008537.1、AC008560.1、AC008575.1、AC008575.2、AC008687.1、AC008687.4、AC008687.8、AC008695.1、AC008735.6、AC008750.8、AC008758.1、AC008758.4、AC008758.5、AC008758.6、AC008763.2、AC008763.3、AC008764.1、AC008764.4、AC008770.2、AC008770.3、AC008878.1、AC008878.2、AC008878.3、AC008982.1、AC008982.3、AC009014.1、AC009086.2、AC009119.2、AC009122.1、AC009133.6、AC009163.2、AC009163.4、AC009286.3、AC009336.2、AC009477.2、AC009690.1、AC009690.3、AC009779.3、AC010132.3、A. C010255.3、AC010319.2、AC010323.1、AC010325.1、AC010326.2、AC010327.1、AC010422.3、AC010422.5、AC010422.6、AC010463.1、AC010487.3、AC010522.1、AC010531.1、AC010542.3、AC010547.4、AC010547.5、AC010615.4、AC010616.1、AC010619.1、AC010646.1、AC010724.2、AC011005.1、AC011043.1、AC011043.2、AC011195.2、AC011295.1、AC011346.1、AC011448.1、AC011452.1、AC011455.3、AC011455.4、AC011462.1、AC011473.4、AC011479.1、AC011498.4、AC011499.1、AC011511.1、AC011511.4、AC011530.1、AC011604.2、AC011841.1、AC012184.2、AC012254.2、AC012309.1、AC012314.1、AC012314.10、AC012314.11、AC012314.12、AC012314.4、AC012314.5、AC012314.6、AC012314.8、AC012531.3、AC012651.1、AC013269.1、AC013271.1、AC013394.1、AC013470.2、AC015688.5、AC015802.6、AC015813.2、AC017081.3、AC017081.4、AC017081.5、AC017083.4、AC018512.1、AC018523.2、AC018554.3、AC018630.6、AC018709.1、AC018755.2、AC018793.1、AC018793.2、AC018793.3、AC018793.4、AC018793.5、AC019117.3、AC020636.2、AC020909.1、AC020914.1、AC020915.1、AC020915.2、AC020915.6、AC020922.1、AC020934.3、AC021072.1、AC022016.2、AC022167.5、AC022335.1、AC022384.1、AC022400.6、AC022826.2、AC023055.1、AC023491.2、AC023509.3、AC024592.3、AC024940.1、AC024940.6、AC025165.3、AC025263.2、AC025283.2、AC025287.4、AC025594.2、AC026369.8、AC026398.1、AC026461.4、AC026464.1、AC026464.3、AC026464.4、AC026786.1、AC026954.2、AC027796.3、AC034102.2、AC036214.3、AC037459.1、AC037482.2、AC037482.3、AC040162.1、AC040162.4、AC044810.8、AC046185.1、AC048338.1、AC051649.2、AC053481.5、AC055811.2、AC058822.1、AC064853.2、AC064853.3、AC064853.4、AC064853.5、AC064853.6、AC067968.1、AC068234.1、AC068533.4、AC068547.1、AC068580.4、AC068631.2、AC068775.1、AC068775.2、AC068790.8、AC068896.1、AC068946.1、AC068987.5、AC069257.3、AC069368.1、AC069503.2、AC069544.2、AC072022.1、AC073082.1、AC073111.3、AC073111.5、AC073264.3、AC073508.2、AC073610.2、AC073610.3、AC073612.1、AC073896.1、AC074143.1、AC078927.1、AC079325.2、AC079447.1、AC079594.2、AC083800.1、AC083902.2、AC084337.2、AC087289.3、AC087498.1、AC087632.1、AC090004.1、AC090227.1、AC090360.1、AC090527.2、AC090958.3、AC091167.3、AC091167.7、AC091167.8、AC091304.7、AC091491.1、AC091551.1、AC091959.3、AC091980.2、AC092017.3、AC092042.3、AC092073.1、AC092111.3、AC092143.1、AC092329.3、AC092442.1、AC092587.1、AC092647.5、AC092718.3、AC092718.8、AC092821.1、AC092824.3、AC092835.1、AC093155.3、AC093227.3、AC093423.3、AC093525.1、AC093525.2、AC093668.1、AC093762.1、AC093762.2、AC093762.3、AC093899.2、AC096582.3、AC096887.1、AC097372.1、AC097495.1、AC097637.1、AC097662.2、AC098484.3、AC098650.1、AC098850.4、AC099329.3、AC099489.1、AC099518.3、AC099811.2、AC099850.2、AC100868.1、AC104109.3、AC104151.1、AC104304.1、AC104452.1、AC104532.1、AC104534.3、AC104581.1、AC104581.3、AC104662.2、AC104836.1、AC105001.2、AC105052.1、AC106774.10、AC106774.5、AC106774.6、AC106774.7、AC106774.8、AC106774.9、AC106782.1、AC106886.5、AC107871.1、AC108488.2、AC108750.1、AC108941.2、AC109583.3、AC110275.1、AC112229.3、AC112484.1、AC113189.6、AC113189.9、AC113331.2、AC113554.2、AC114296.1、AC114490.2、AC115220.1、AC116366.3、AC116565.1、AC117457.1、AC118470.1、AC118553.2、AC119396.1、AC119674.2、AC120057.3、AC120114.5、AC124312.1、AC126755.2、AC127537.5、AC127537.6、AC127537.8、AC129492.3、AC131097.2、AC131160.1、AC133551.1、AC133555.3、AC134669.2、AC134772.2、AC135050.2、AC135068.1、AC135068.2、AC135 068.3、AC135068.8、AC135178.2、AC135586.2、AC136352.3、AC136352.4、AC136428.1、AC136612.1、AC 136616.1, AC136616.2, AC136616.3, AC137834.1, AC138517.2, AC138647.1, AC138696.1, AC138811.2, AC138894.1, AC138969.1, AC139530.2, AC139677.1, AC139677.2, AC140504.1, AC141272.1, AC1423 91.1, AC142525.4, AC145029.2, AC145212.1, AC145212.2, AC171558.1, AC171558.3, AC171558.5, AC171558.6, AC187653.1, AC207056.1, AC209232.1, AC209539.2, AC210544.1, AC213203.1, AC229888.1 AC229888.10, AC229888.2, AC229888.3, ​​AC229888.4, AC229888.5, AC229888.6, AC229888.7, AC229888.8, AC229888.9, AC233282.1, AC233282.2, AC233723.1, AC233724.12, AC233724.16, AC233724.1. 7, AC233724.18, AC233724.19, AC233724.20, AC233724.21, AC233724.6, AC233755.1, AC233755.2, AC233992.2, AC234301.1, AC234301.3, AC234635 .1、AC234635.3、AC234635.4、AC234635.5、AC236040.1、AC239612.1、AC23 9618.1、AC239618.2、AC239618.3、AC239618.4、AC239618.5、AC239618.6、A C239618.7、AC239618.9、AC239799.1、AC240274.1、AC241401.1、AC241409 .2、AC241410.1、AC241556.3、AC241556.4、AC241640.1、AC241640.2、AC24 1640.4, AC242528.1, AC242528.2, AC243547.3, AC243733.1, AC243734.1, AC243756.1, AC243790.1, AC243967.1, AC244196.1, AC244196.2, AC244196 .3、AC244196.4、AC244196.5、AC244197.3、AC244216.4、AC244216.5、AC24 4226.1、AC244226.2、AC244472.1、AC244472.2、AC244472.3、AC244472.4、 AC244472.5、AC244489.1、AC244489.2、AC244517.10、AC244517.6、AC2450 33.1、AC245034.2、AC245078.1、AC245088.2、AC245088.3、AC245369.1、AC2 45369.2, AC245369.3, AC245369.4, AC245369.6, AC245427.1, AC245427.3, AC245427.4, AC245427.5, AC245427.6, AC245427.7, AC245427.8, AC24542 7.9, AC245748.1, AC247036.3, AC247036.4, AC247036.5, AC247036.6, AC254560.1, AC254788.1, AC254788.2, AC254952.1, AC255093.3, AC255093.5AC256236.1、AC256236.2、AC256236.3、AC256300.2、AC256309.2、AC270107.1、AC270107.10、AC270107.12、AC270107.2、AC270107.3、AC270107.4、AC270107.5、AC270107.7、AC270107.8、AC270107.9、AC270227.1、AC270306.4、AC275455.2、ACAA1、ACAA2、ACACA、ACACB、ACAD10、ACAD11、ACAD8、ACAD9、ACADL、ACADM、ACADS、ACADSB、ACADVL、ACAN、ACAP1、ACAP2、ACAP3、ACAT1、ACAT2、ACBD3、ACBD4、ACBD5、ACBD6、ACBD7、ACCS、ACCSL、ACD、ACE、ACE2、ACER1、ACER2、ACER3、ACHE、ACIN1、ACKR1、ACKR2、ACKR3、ACKR4、ACLY、ACMSD、ACO1、ACO2、ACOD1、ACOT1、ACOT11、ACOT12、ACOT13、ACOT2、ACOT4、ACOT6、ACOT7、ACOT8、ACOT9、ACOX1、ACOX2、ACOX3、ACOXL、ACP1、ACP2、ACP4、ACP5、ACP6、ACP7、ACPP、ACR、ACRBP、ACRV1、ACSBG1、ACSBG2、ACSF2、ACSF3、ACSL1、ACSL3、ACSL4、ACSL5、ACSL6、ACSM1、ACSM2A、ACSM2B、ACSM3、ACSM4、ACSM5、ACSM6、ACSS1、ACSS2、ACSS3、ACTA1、ACTA2、ACTB、ACTBL2、ACTC1、ACTG1、ACTG2、ACTL10、ACTL6A、ACTL6B、ACTL7A、ACTL7B、ACTL8、ACTL9、ACTN1、ACTN2、ACTN3、ACTN4、ACTR10、ACTR1A、ACTR1B、ACTR2、ACTR3、ACTR3B、ACTR3C、ACTR5、ACTR6、ACTR8、ACTRT1、ACTRT2、ACTRT3、ACVR1、ACVR1B、ACVR1C、ACVR2A、ACVR2B、ACVRL1、ACY1、ACY3、ACYP1、ACYP2、AD000671.1、AD000671.2、ADA、ADA2、ADAD1, ADAD2, ADAL, ADAM10, ADAM11, ADAM12, ADAM15, ADAM17, ADAM18, ADAM19, ADAM2, ADAM20, ADAM21, ADAM22, ADAM23, ADAM28, ADAM29, ADAM30, ADAM32, ADAM33, ADAM7, ADAM8, ADAM9, ADAMDEC1, ADAMTS1, ADAMTS10, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15, ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS 19、ADAMTS2、ADAMTS20、ADAMTS3、ADAMTS4、ADAMTS5、ADAMTS6、ADAMTS7、ADAMTS8、ADAMTS9、ADAMTSL1、ADAMTSL2、ADAMTSL3、ADAMTSL4、ADAMTSL5、ADAP1、ADAP2、ADAR、ADARB1、ADARB2、ADAT1、ADAT2、ADAT3、ADCK1、ADCK2、ADCK5、ADCY1、ADCY10、ADCY2、ADCY3、ADCY4、ADCY5、ADCY6、ADCY7、ADCY8、ADCY9、 ADCYAP1、ADCYAP1R1、ADD1、ADD2、ADD3、ADGB、ADGRA1、ADGRA2、ADGRA3、ADGRB1、ADGRB2、ADGRB3、ADGRD1、ADGR2、ADGRE1、ADGRE2、ADGRE3、ADGRE5、ADGRE1 GRF1、ADGRF2、ADGRF3、ADGRF4、ADGRF5、ADGRG1、ADGRG2、ADGRG3、ADGRG4、ADGRG5、ADGRG6、ADGRG7、ADGRL1、ADGRL2、ADGRL3、ADGRL4、ADGRV1、ADH1A、ADGRL1 H1B、ADH1C、ADH4、ADH5、ADH6、ADH7、ADHFE1、ADI1、ADIG、ADIPOQ、ADIPOR1、ADIPOR2、ADIRF、ADK、ADM、ADM2、ADM5、ADNP、ADNP2、ADO、ADORA1、ADORA2A、 ADORA2B、ADORA3、ADPGK、ADPRH、ADPRHL1、ADPRHL2、ADPRM、ADRA1A、ADRA1B、ADRA1D、ADRA2A、ADRA2B、ADRA2C、ADRB1、ADRB2、ADRB3、ADRM1、ADSL、ADSS、ADSSL1、ADTRP、AEBP1、AEBP2、AEN、AES、AF130351.1、AF241726.2、 AFAP1, AFAP1L1, AFAP1L2, AFDN, AFF1, AFF2, AFF3, AFF4, AFG1L, AFG3L2, AFM, AFMID, AFP, AFTPH, AGA, AGAP1, AGAP2, AGAP3, AGAP4, AGAP5, AGAP6, AGAP9, AGBL1, AGBL2, AGBL3, AGBL4, AGBL5, AGER, AGFG1, AGFG2, AGGF1, AGK, AGL, AGMAT, AGMO, AGO1 、AGO2、AGO3、AGO4、AGPAT1、AGPAT2、AGPAT3、AGPAT4、AGPAT5、AGPS、AGR2、AGR3、AG RN、AGRP、AGT、AGTPBP1、AGTR1、AGTR2、AGTRAP、AGXT、AGXT2、AHCTF1、AHCY、AHCYL1 、AHCYL2、AHDC1、AHI1、AHNAK、AHNAK2、AHR、AHRR、AHSA1、AHSA2、AHSG、AHSP、AICD A、AIDA、AIF1、AIF1L、AIFM1、AIFM2、AIFM3、AIG1、AIM2、AIMP1、AIMP2、AIP、AIPL1、 AIRE、 AJAP1、AJUBA、AK1、AK2、AK3、AK4、AK5、AK6、AK7、AK8、AK9、AKAIN1、AKAP1、A KAP10、AKAP11、AKAP12、AKAP13、AKAP14、AKAP17A、AKAP2、AKAP3、AKAP4、AK AP5、AKAP6、AKAP7、AKAP8、AKAP8L、AKAP9、AKIP1、AKIRIN1、AKIRIN2、AKNA、 AKNAD1、AKR1A1、AKR1B1、AKR1B10、AKR1B15、AKR1C1、AKR1C2、AKR1C3、AKR1 C4、AKR1D1、AKR1E2、AKR7A2、AKR7A3、AKR7L、AKT1、AKT1S1、AKT2、AKT3、AKT IP、AL020996.2、AL021154.3、AL021546.1、AL021997.3、AL022238.4、AL02 2318.4, AL024498.2, AL031708.1, AL032819.3, AL033529.1, AL035425.2, AL035460.1, AL049634.2, AL049650.1, AL049697.1, AL049779.1, AL04983 9.2、AL049844.1、AL049844.3、AL080251.1、AL096814.1、AL096870.1、AL1 09810.2、AL109811.4、AL109827.1、AL109936.3、AL109936.4、AL110118.2 、AL110118.4、AL117258.1、AL117339.5、AL117348.2、AL121581.1、AL1215 94.3、AL121722.1、AL121753.1、AL121758.1、AL121845.2、AL121845.3、AL 132671.2, AL132780.3, AL133352.1, AL133414.1, AL133414.2, AL136295.1, AL136295.3, AL136295.4, AL136295.5, AL136373.1, AL136531.2, AL138 694.1, AL138752.2, AL138826.1, AL139011.2, AL139260.3, AL139300.1, AL139353.1, AL157392.5, AL159163.1, AL160275.1, AL160276.1, AL160396.2、AL161669.4、AL161911.1、AL162231.1、AL162231.3、AL163195.3 、AL163636.2、AL353572.3、AL353588.1、AL354761.2、AL354822.1、A L355102.2, AL355315.1, AL355860.1, AL355916.3, AL355987.1, AL355987.3, AL356585.9, AL357673.1, AL358075.4, AL359736.1, AL359 736.3, AL359922.1, AL360181.3, AL360181.5, AL365205.1, AL365214.3, AL365232.1, AL365273.2, AL391650.1, AL449266.1, AL451007 .3, AL512428.1, AL512506.3, AL512785.2, AL513165.2, AL513523.10, AL513523.9, AL583836.1, AL589666.1, AL590132.1, AL590560.1. 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BUB 1、BUB1B、BUB1B-PAK6、BUB3、BUD13、BUD23、BUD31、BVES、BX004987. 1、BX072566.1、BX088645.1、BX248244.1、BX248413.4、BX248415.1 、BX248516.1、BX276092.9、BYSL、BZW1、BZW2、C10orf10、C10orf105、C10orf107、C10o rf113、C10orf120、C10orf126、C10orf128、C10orf142、C10orf35、C10orf53、C10orf55 、C10orf62、C10orf67、C10orf71、C10orf76、C10orf82、C10orf88、C10orf90、C10orf9 5、C10orf99、C11orf1、C11orf16、C11orf21、C11orf24、C11orf40、C11orf42、C11orf45 、C11orf49、C11orf52、C11orf53、C11orf54、C11orf57、C11orf58、C11orf63、C11orf65 、C11orf68、C11orf70、C11orf71、C11orf74、C11orf80、C11orf84、C11orf86、C11orf87 、C11orf88、C11orf91、C11orf94、C11orf95、C11orf96、C11orf97、C11orf98、C12orf1 0、C12orf29、C12orf4、C12orf40、C12orf42、C12orf43、C12orf45、C12orf49、C12orf50 、C12orf54、C12orf56、C12orf57、C12orf60、C12orf65、C12orf66、C12orf71、C12orf73、C12orf74、C12orf75、C12orf76、C13orf42、C14orf105、C14orf119、C14orf132、C14orf159、C14orf166、C14orf177、C14orf178、C14orf180、C14orf2、C14orf28、C14orf37、C14orf39、C14orf79、C14orf80、C14orf93、C15orf38-AP3S2、C15orf39、C15orf40、C15orf41、C15orf48、C15orf52、C15orf53、C15orf59、C15orf61、C15orf62、C15orf65、C16orf45、C16orf46、C16orf52、C16orf54、C16orf58、C16orf59、C16orf62、C16orf70、C16orf71、C16orf72、C16orf74、C16orf78、C16orf82、C16orf86、C16orf87、C16orf89、C16orf90、C16orf91、C16orf92、C16orf95、C16orf96、C17orf100、C17orf105、C17orf107、C17orf113、C17orf47、C17orf49、C17orf50、C17orf51、C17orf53、C17orf58、C17orf62、C17orf64、C17orf67、C17orf74、C17orf75、C17orf78、C17orf80、C17orf97、C17orf98、C17orf99、C18orf21、C18orf25、C18orf32、C18orf54、C18orf63、C18orf8、C19orf12、C19orf18、C19orf24、C19orf25、C19orf33、C19orf35、C19orf38、C19orf44、C19orf47、C19orf48、C19orf53、C19orf54、C19orf57、C19orf60、C19orf66、C19orf67、C19orf68、C19orf70、C19orf71、C19orf73、C19orf81、C19orf84、C1D、C1GALT1、C1GALT1C1、C1GALT1C1L、C1orf100、C1orf105、C1orf109、C1orf112、C1orf115、C1orf116、C1orf122、C1orf123、C1orf127、C1orf131、C1orf141、C1orf146、C1orf158、C1orf159、C1orf162、C1orf167、C1orf174、C1orf185、C1orf186、C1orf189、C1orf194、C1orf198、C1orf21、C1orf210、C1orf216、C1orf226、C1orf228、C1orf232、C1orf27、C1orf35、C1orf43、C1orf50、C1orf52、C1orf53、C1orf54、C1orf56、C1orf61、C1orf64、C1orf68、C1orf74、C1orf87、 、C1orf94、C1QA、C1QB、C1QBP、C1QC、C1QL1、C1QL2、C1QL3、C1QL4、C1QTNF1、C1QTNF12、C1QTNF2、C1QTNF3、C1QTNF3-AMACR、C1QTNF4、C1QTNF5、C1QTNF6、C1QTNF7、C1QTNF8 、C1QTNF9、C1QTNF9B、C1R、C1RL、C1S、C2、C20orf141、C20orf144、C20orf173、C20orf194、C20orf196、C20orf202、C20orf204、C20orf24、C20orf27、C20orf85、C20orf96、C21orf140、C21orf2、C21orf33、C21orf58、C21orf59、C21orf62、C21orf91、C22orf15、C22orf23、C22orf31、C22orf39、C22orf42、C22orf46、C2CD2、C2CD2L、C2CD3、C2CD4A、C2CD4B、C2CD4C、C2CD4D、C2CD5、C2CD6、C2orf15、C2orf16、C2orf40、C2orf42、C2orf49 ,C2orf50,C2orf54,C2orf66,C2orf68,C2orf69,C2orf70,C2orf71,C2orf72,C2orf73,C2orf74,C2orf76,C2orf78,C2orf80,C2orf81,C2orf82,C2orf83,C2orf88,C2orf91,C3,C3AR1,C3orf14,C3orf18,C3orf20,C3orf22,C3orf30,C3orf33,C3orf35,C3orf36,C3orf38,C3orf49,C3orf52,C3orf56 、C3orf58、C3orf62、C3orf67、C3orf70、C3orf80、C3orf84、C3orf85、C4A、C4B、C4B_2、C4BPA、C4BPB、C4orf17、C4orf19、C4orf22、C4orf26、C4orf3、C4 orf32、C4orf33、C4orf36、C4orf45、C4orf46、C4orf47、C4orf48、C4orf50、C4orf51、C5、C5AR1、C5AR2、C5orf15、C5orf22、C5orf24、C5orf30、C5orf34、 C5orf38, C5orf42, C5orf46, C5orf47, C5orf49, C5orf51, C5orf52, C5orf56, C5orf58, C5orf60, C5orf63, C5orf67, C6, C6orf10, C6orf106, C6orf118, C6orf120, C6orf132, C6orf136, C6orf141, C6orf15, C6orf163, C6orf201, C6orf203, C6orf222, C6orf223, C6orf226, C6orf229, C6orf47, C6orf48, C 6orf52、C6orf58、C6orf62、C6orf89、C7、C7、C7orf25、C7orf26、C7orf31、C7orf33、C7orf34、C7orf43、C7orf49、C7orf50、C7orf55-LUC7L2、C7orf57、C7orf61、C7orf72、C7orf73、C7orf77、C8A、C8B、C8G、C8orf22、C8orf33、C8orf34、C8orf37、C8orf4、C8orf44、C8orf44-SGK3、C8orf46、C8orf48、C8orf58、C8orf59、C8orf74、C8orf76、C8orf82、C8orf86、C8orf88、C8orf89、C9、C9orf116、C9orf129、C9orf131、C9orf135、C9orf152、C9orf153、C9orf16、C9orf172、C9orf24、C9orf3、C9orf40、C9orf43、C9orf47、C9orf50、C9orf57、C9orf64、C9orf66、C9orf72、C9orf78、C9orf84、C9orf85、C9orf92、CA1、CA10、CA11、CA12、CA13、CA14、CA2、CA3、 、CA4、CA5A、CA5B、CA6、CA7、CA8、CA9、CAAP1、CAB39、CAB39L、CABIN1、CABLES1、CABLES2、CABP1、CABP2、CABP4、CABP5、CABP7、CABS1、CABYR、CACFD1、CACHD1、CACNA1A 、CACNA1B、CACNA1C、CACNA1D、CACNA1E、CACNA1F、CACNA1G、CACNA1H、CACNA1I、CACNA1S、CACNA2D1、CACNA2D2、CACNA2D3、CACNA2D4、CACNB1、CACNB2、CACNB3、CACNB4、CACNG 1、CACNG2、CACNG3、CACNG4、CACNG5、CACNG6、CACNG7、CACNG8、CACTIN、CACUL1、CACY BP、CAD、CADM1、CADM2、CADM3、CADM4、CADPS、CADPS2、CAGE1、CALB1、CALB2、CALCA、C ALCB、CALCOCO1、CALCOCO2、CALCR、CALCRL、CALD1、CALHM1、CALHM2、CALHM3、CALM1、 CALM2、CALM3、CALML3、CALML4、CALML5、CALML6、CALN1、CALR、CALR3、CALU、CALY、CAM K1、CAMK1D、CAMK1G、CAMK2A、CAMK2B、CAMK2D、CAMK2G、CAMK2N1、CAMK2N2、CAMK4、CA MKK1, CAMKK2, CAMKMT, CAMKV, CAMLG, CAMP, CAMSAP1, CAMSAP2, CAMSAP3, CAMTA1, CA MTA2、CAND1、CAND2、CANT1、CANX、CAP1、CAP2、CAPG、CAPN1、CAPN10、CAPN11、CAPN12 、CAPN13、CAPN14、CAPN15、CAPN2、CAPN3、CAPN5、CAPN6、CAPN7、CAPN8、CAPN9、CAPNS1 、CAPNS2、CAPRIN1、CAPRIN2、CAPS、CAPS2、CAPSL、CAPZA1、CAPZA2、CAPZA3、CAPZB、CARD10、CARD11、CARD14、CARD16、CARD17、CARD18、CARD19、CARD6、CARD8、CARD9、CARF、CARHSP1、CARM1、CARMIL1、CARMIL2、CARMIL3、CARNMT1、CARNS1、CARS、CARS2、CARTPT、CASC1、CASC10、CASC3、CASC4、CASD1、CASK、CASKIN1、CASKIN2、CASP1、CASP10、CASP12、CASP14、CASP2、CASP3、CASP4、CASP5、CASP6、CASP7、CASP8、CASP8AP2、CASP9、CASQ1、CASQ2、CASR、CASS4、CAST、CASTOR1、CASTOR2、CASZ1、CAT、CATIP、CATSPER1、CATSPER2、CATSPER3、CATSPER4、CATSPERB、CATSPERD、CATSPERE、CATSPERG、CATSPERZ、CAV1、CAV2、CAV3、CAVIN1、CAVIN2、CAVIN3、CAVIN4、CBARP、CBFA2T2、CBFA2T3、CBFB 、CBL、CBLB、CBLC、CBLL1、CBLN1、CBLN2、CBLN3、CBLN4、CBR1、CBR3、CBR4、CBS、CBSL、CBWD1、CBWD2、CBWD3、CBWD5、CBWD6、CBX1、CBX2、CBX3、CBX4、CBX5、CBX6、CBX7、CBX8、CBY1、CBY3、CC2D1A、CC2D1B、CC2D2A、CC2D2B、CCAR1、CCAR2、CCBE1、CCDC102A 、CCDC102B、CCDC103、CCDC105、CCDC106、CCDC107、CCDC110、CCDC112、CCDC113、CCDC114、CCDC115、CCDC116、CCDC117、CCDC12、CCDC120、CCDC121、CCDC122、CCDC124、CCDC125、CCDC126、CCDC127、CCDC129、CCDC13、CCDC130、CCDC134、CCDC136、CCDC137、CCDC138、CCDC14、CCDC140、CCDC141、CCDC142、CCDC144A、CCDC144NL、CCDC146、CCDC148、CCDC149、CCDC15、CCDC150、CCDC151、CCDC152、CCDC153、CCDC154、CCDC155、CCDC157、CCDC158、CCDC159、CCDC160、CCDC163、CCDC166、CCDC167、CCDC168、CCDC169、CCDC169-SOHLH2、CCDC17、CCDC170、CCDC171、CCDC172、CCDC173、CCDC174、CCDC175、CCDC177、CCDC178、CCDC179、CCDC18、CCDC180、CCDC181、CCDC182、CCDC183、CCDC184、CCDC185、CCDC186、CCDC187、CCDC188、CCDC189、CCDC190、CCDC191、CCDC192、CCDC194、CCDC195、CCDC196、CCDC197、CCDC22、CCDC24、CCDC25、CCDC27、CCDC28A、CCDC28B、CCDC3、CCDC30 、CCDC32、CCDC33、CCDC34、CCDC36、CCDC38、CCDC39、CCDC40、CCDC42、CCDC43、CCDC47、CCDC50、CCDC51、CCDC54、CCDC57、CCDC58、CCDC59、CCDC6、CCDC60、CCDC61、CCDC62 、CCDC63、CCDC65、CCDC66、CCDC68、CCDC69、CCDC7、CCDC70、CCDC71、CCDC71L、CCDC73、CCDC74A、CCDC74B、CCDC77、CCDC78、CCDC 8、CCDC80、CCDC81、CCDC82、CCDC83、CCDC84、CCDC85A、CCDC85B、CCDC85C、CCDC86、CCDC87、CCDC88A、CCDC88B、CCDC88C、CCDC89 ,CCDC9,CCDC90B,CCDC91,CCDC92,CCDC93,CCDC94,CCDC96,CCDC97,CCER1,CCER2,CCHCR1,CCIN,CCK,CCKAR,CCKBR,CCL1,CCL11,CCL13,CCL14,CCL15,CCL15-CCL14,CCL16,CCL17,CCL18,CCL19,CCL2,CCL20,CCL21,CCL22,CCL23,CCL24,CCL25,CCL26,CCL27,CCL28,CCL3,CCL3L1,CCL3L3,CCL4,CCL4L2,CCL5,CCL7,CCL8,CCM2,CCM2L,CCNA1,CCNA2,CCNB1,CCNB1IP1,CC NB2、CCNB3、CCNC、CCND1、CCND2、CCND3、CCNDBP1、CCNE1、CCNE2、CCNF、CCNG1、CCNG2、CCNH、CCNI、CCNI2、CCNJ、CCNJL、CCNK、CCNL1、CCNL2、CCNO、CCNT1、CCNT2、CCNY、CCNYL1、CCP110、CCPG 1. 、CD14、CD151、CD160、CD163、CD163L1、CD164、CD164L2、CD177、CD180、CD19、CD1A、CD1B、CD1C、CD1D、CD1E、CD2、CD200、CD200R1、CD200R1L、CD2 07、CD209、CD22、CD226、CD24、CD244、CD247、CD248、CD27、CD274、CD276、CD28、CD2AP、CD2BP2、CD300A、CD300C、CD300E、CD300LB、CD300LD、CD30LD 0LF、CD300LG、CD302、CD320、CD33、CD34、CD36、CD37、CD38、CD3D、CD3E、CD3EAP、CD3G、CD4、CD40、CD40LG、CD44、CD46、CD47、CD48、CD5、CD52、CD5 3、CD55、CD58、CD59、CD5L、CD6、CD63、CD68、CD69、CD7、CD70、CD72、CD74、CD79A、CD79B、CD80、CD81、CD82、CD83、CD84、CD86、CD8A、CD8B、CD9、CD9 3、CD96、CD99、CD99L2、CDA、CDADC1、CDAN1、CDC123、CDC14A、CDC14B、CDC16、CDC20 、CDC20B、CDC23、CDC25A、CDC25B、CDC25C、CDC26、CDC27、CDC34、CDC37、CDC37L1、CDC40、CDC42、CDC42BPA、CDC42BPB、CDC42BPG、CDC42EP1、CDC42 EP2、CDC42EP3、CDC42EP4、CDC42EP5、CDC42SE1、CDC42SE2、CDC45、CDC5L、CDC6、CDC7、CDC73、CDCA2、CDCA3、CDCA4、CDCA5、CDCA7、CDCA7L、CDCA8、C DCP1、CDCP2、CDH1、CDH10、CDH11、CDH12、CDH13、CDH15、CDH16、CDH17、CDH18、CDH19、CDH2、CDH20、CDH22、CDH23、CDH24、CDH26、CDH3、CDH4、CDH5、CDH1 DH6、CDH7、CDH8、CDH9、CDHR1、CDHR2、CDHR3、CDHR4、CDHR5、CDIP1、CDIPT、CDK1、CDK10、CDK11A、CDK11B、CDK12、CDK13、CDK14、CDK15、CDK16、CDK17 、CDK18、CDK19、CDK2 、CDK20、CDK2AP1、CDK2AP2、CDK3、CDK4、CDK5、CDK5R1、CDK5R2、CDK5RAP1、CDK5RAP2 ,CDK5RAP3,CDK6,CDK7,CDK8,CDK9,CDKAL1,CDKL1,CDKL2,CDKL3,CDKL4,CDKL5,CDKN1A,CDKN1B,CDKN1C,CDKN2A,CDKN2AIP,CDKN2AIPNL,CDKN2B,CDKN2C,CDKN2D,CDKN3,CDNF,CDO1,CDON,CDPF1,CDR1,CDR2,CDR2L,CDRT1,CDRT15,CDRT15L2,CDRT4,CDS1,CDS2,CDSN,CDT1,CDV3,CDX1,CDX2,CDX4,CDY1,CDY1B,CDY2A,CDY2B,CDYL 、CDYL2、CEACAM1、CEACAM16、CEACAM19、CEACAM20、CEACAM21、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEA CAM7、CEACAM8、CEBPA、CEBPB、CEBPD、CEBPE、CEBPG、CEBPZ、CEBPZOS、CECR2、CEL、CELA1、CELA2A、CELA2B、 CELA3A、CELA3B、CELF1、CELF2、CELF3、CELF4、CELF5、CELF6、CELSR1、CELSR2、CELSR3、CEMIP、CEMP1、CEND 1、CENPA、CENPB、CENPBD1、CENPC、CENPE、CENPF、CENPH、CENPI、CENPJ、CENPK、CENPL、CENPM、CENPN、CENPO 、CENPP、CENPQ、CENPS、CENPS-CORT、CENPT、CENPU、CENPV、CENPVL1、CENPVL2、CENPV L3、CENPW、CENPX、CEP104、CEP112、CEP120、CEP126、CEP128、CEP131、CEP135、CEP152 CEP162, CEP164, CEP170, CEP170B, CEP19, CEP192, CEP250, CEP290, CEP295, CEP295NL, CEP350, CEP41, CEP44, CEP55, CEP57, CEP57L1, CEP63, CEP68, CEP70, CEP72, CEP76, CEP78, CEP83, CEP85, CEP85L, CEP89, CEP95, CEP97, CEPT1, CER1, CERCAM, CERK 、CERKL、CERS1、CERS2、CERS3、CERS4、CERS5、CERS6、CES1、CES2、CES3、CES4A、CES5A、CETN1、CETN2、CETN3、CETP、CFAP100、CFAP126、CFAP157、CFAP161、CFAP20、CFAP206、CFAP221、CFAP36、CFAP43、CFAP44、CFAP45、CFAP46、CFAP47、CFAP52、CFAP53、CFAP54、CFAP57、CFAP58、CFAP61、CFAP65、CFAP69、CFAP70、CFAP73、CFAP74、CFAP77、CFAP97、CFAP99、CFB、CFC1、CFC1B、CFD、CFDP1、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI、CFL1、CFL2、CFLAR、CFP、CFTR、CGA、CGB1、CGB2、CGB3、CGB5、CGB7、CGB8、CGGBP1、CGN、CGNL1、CGREF1、CGRRF1、CH25H、CHAC1、CHAC2、CHAD、CHADL、CHAF1A、CHAF1B、CHAMP1、CHAT、CHCHD1、CHCHD10、CHCHD2、CHCHD3、CHCHD4、CHCHD5、CHCHD6、CHCHD7、CHD1、CHD1L、CHD2、CHD3、CHD4、CHD5、CHD6、CHD7、CHD8、CHD9、CHDH、CHEK1、CHEK2、CHERP、CHFR、CHGA、CHGB、CHI3L1、CHI3L2、CHIA、CHIC1、CHIC2、CHID1、CHIT1、CHKA、CHKB、CHKB-CPT1B、CHL1、CHM、CHML、CHMP1A、CHMP1B、CHMP2A、CHMP2B、CHMP3、CHMP4A、CHMP4B、CHMP4C、CHMP5、CHMP6、CHMP7、CHN1、CHN2、CHODL、CHORDC1、CHP1、CHP2、CHPF、CHPF2、CHPT1、CHRAC1、CHRD、CHRDL1、CHRDL2、CHRFAM7A、CHRM1、CHRM2、CHRM3、CHRM4、CHRM5、CHRNA1、CHRNA10、CHRNA2、CHRNA3、CHRNA4、CHRNA5、CHRNA6、CHRNA7、CHRNA9、CHRNB1、CHRNB2、CHRNB3、CHRNB4、CHRND、CHRNE、CHRNG、CHST1、CHST10、CHST11、CHST12、CHST13、CHST14、CHST15、CHST2、CHST3、CHST4、CHST5、CHST6、CHST7、CHST8、CHST9、CHSY1、CHSY3、CH TF18、CHTF8、CHTOP、CHUK、CHURC1、CHURC1-FNTB、CIAO1、CIAPIN1、CIART、CIB1、CIB2、CIB3、CIB4、CIC、CIDEA、CIDEB、CIDEC、CIITA、CILP、CILP2、CINP、CIP C、CIR1、CIRBP、CISD1、CISD2、CISD3、CISH、CIT、CITED1、CITED2、CITED4、CIZ1、CKAP2、CKAP2L、CKAP4、CKAP5、CKB、CKLF、CKLF-CMTM1、CKM、CKMT1A、CKMT1B 、CKMT2、CKS1B、CKS2、CLASP1、CLASP2、CLASRP、CLC、CLCA1、CLCA2、CLCA4、CLCC1、CLCF1、CLCN1、CLCN2、CLCN3、CLCN4、CLCN5、CLCN6、CLCN7、CLCNKA、CLCNKB、 、CLDN1、CLDN10、CLDN11、CLDN12、CLDN14、CLDN15、CLDN16、CLDN17、CLDN18、CLDN19 、CLDN2、CLDN20、CLDN22、CLDN23、CLDN24、CLDN25、CLDN3、CLDN34、CLDN4、CLDN5、CLDN6、CLDN7、CLDN8、CLDN9、CLDND1、CLDND2、 CLEC10A、CLEC11A、CLEC12A、CLEC12B、CLEC14A、CLEC16A、CLEC17A、CLEC18A、CLEC18B、CLEC18C、CLEC19A、CLEC1A、CLEC1B、CLE C20A、CLEC2A、CLEC2B、CLEC2D、CLEC2L、CLEC3A、CLEC3B、CLEC4A、CLEC4C、CLEC4D、CLEC4E、CLEC4F、CLEC4G、CLEC4M、CLEC5A、CLEC6A、CLEC7A、CLEC9A、CLECL1、CLGN、CLHC1、CLIC1、CLIC2、CLIC3、CLIC4、CLIC5、CLIC6、CLINT1、CLIP1、CLIP2、CLIP3、CLIP4 , CLK1, CLK2, CLK3, CLK4, CLLU1, CLLU1OS, CLMN, CLMP, CLN3, CLN5, CLN6, CLN8, CLNK, CLNS1A, CLOCK, CLP1, CLPB, CLPP, CLPS, CLPSL1, CLPSL2, CL PTM1, CLPTM1L, CLPX, CLRN1, CLRN2, CLRN3, CLSPN, CLSTN1, CLSTN2, CLSTN3, CLTA, CLTB, CLTC, CLTCL1, CLU, CLUAP1, CLUH, CLUL1, CLVS1, CLVS2, C LYBL、CMA1、CMAS、CMBL、CMC1、CMC2、CMC4、CMIP、CMKLR1、CMPK1、CMPK2、CMSS1、CMTM1、CMTM2、CMTM3、CMTM4、CMTM5、CMTM6、CMTM7、CMTM8、CMTR1、C MTR2, CMYA5, CNBD1, CNBD2, CNBP, CNDP1, CNDP2, CNEP1R1, CNFN, CNGA1, CNGA2, CNGA3, CNGA4, CNGB1, CNGB3, CNIH1, CNIH2, CNIH3, CNIH4, CNKSR1, CNKSR2, CNKSR3, CNMD, CNN1, CNN2, CNN3, CNNM1, CNNM2, CNNM3, CNNM4, CNOT1, CNOT10, CNOT11, CNOT2, CNOT3, CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8 , CNOT9, CNP, CNPPD1, CNPY1, CNPY2, CNPY3, CNPY4, CNR1, CNR2, CNRIP1, CNST, CNTD1, CNTD2, CNTF, CNTFR, CNTLN, CNTN1, CNTN2, CNTN3, CNTN4, CNT N5、CNTN6、CNTNAP1、CNTNAP2、CNTNAP3、CNTNAP3B、CNTNAP4、CNTNAP5、CNTRL、CNTROB、COA1、COA3、COA4、COA5、COA6、COA7、COASY、COBL、COBLL1、C OCH、COG1、COG2、COG3、COG4、COG5、COG6、COG7、COG8、COIL、COL10A1、COL11A1、COL11A2、COL12A1、COL13A1、COL14A1、COL15A1、COL16A1、COL17A1 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DSG4、DSN1、DSP、DSPP、DST、DSTN、DSTYK、DTD1、DTD2、DTHD1、DTL、DTNA、DTNB、DTNBP1、DTWD1、DTWD2、DTX1、DTX2、DTX3、DTX3L、DTX4、DTYMK、DUOX 1、DUOX2、DUOXA1、DUOXA2、DUPD1、DUS1L、DUS2、DUS3L、DUS4L、DUSP1、DUSP10、DUSP11、DUSP12、DUSP13、DUSP14、DUSP15、DUSP16、DUSP18、DUSP19 、DUSP2、DUSP21、DUSP22、DUSP23、DUSP26、DUSP27、DUSP28、DUSP3、DUSP4、DUSP5、DUSP6、DUSP7、DUSP8、DUSP9、DUT、DUX4、DUX A、DUXB、DVL1、DVL2、DVL3、DWORF、DXO、DYDC1、DYDC2、DYM、DYNAP、DYNC1H1、DYNC1I1、DYNC1I2、DYNC1LI1、DYNC1LI2、DYNC2H1 DYNC2LI1, DYNLL1, DYNLL2, DYNLRB1, DYNLRB2, DYNLT1, DYNL T3, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, DYSF, DYTN, DZANK1 、DZIP1、DZIP1L、DZIP3、E2F1、E2F2、E2F3、E2F4、E2F5、E2F6、E 2F7, E2F8, E4F1, EAF1, EAF2, EAPP, EARS2, EBAG9, EBF1, EBF2 EBF3, EBF4, EBI3, EBLN1, EBLN2, EBNA1BP2, EBP, EBPL, ECD, ECE1, ECE2, ECEL1, ECH1, ECHDC1, ECHDC2, ECHDC3, ECHS1, ECI1 ECI2, ECM1, ECM2, ECSCR, ECSIT, ECT2, ECT2L, EDA, EDA2R, EDAR, EDARADD, EDC3, EDC4, EDDM13, EDDM3A, EDDM3B, EDEM1, EDEM2 EDEM3, EDF1, EDIL3, EDN1, EDN2, EDN3, EDNRA, EDNRB, EDRF1, EEA1, EED, EEF1A1, EE F1A2, EEF1AKMT1, EEF1AKMT2, EEF1AKMT3, EEF1B2, EEF1D, EEF1E1, EEF1E1-BLOC1S5 EEF1G、EEF2、EEF2K、EEF2KMT、EEFSEC、EEPD1、EFCAB1、EFCAB10、EFCAB11、EFCAB12、E FCAB13, EFCAB14, EFCAB2, EFCAB3, EFCAB5, EFCAB6, EFCAB7, EFCAB8, EFCAB9, EFCC1 EFEMP1、EFEMP2、EFHB、EFHC1、EFHC2、EFHD1、EFHD2、EFL1、EFNA1、EFNA2、EFNA3、EFNA4、EFNA5、EFNB1、EFNB2、EFNB3、EFR3A、E FR3B、EFS、EFTUD2、EGF、EGFL6、EGFL7、EGFL8、EGFLAM、EGFR、EGLN1、EGLN2、EGLN3、EGR1、EGR2、EGR3、EGR4、EHBP1、EHBP1L1、E HD1、EHD2、EHD3、EHD4、EHF、EHHADH、EHMT1、EHMT2、EI24、EID1、EID2、EID2B、EID3、EIF1、EIF1AD、EIF1AX、EIF1AY、EIF1B、EIF 2A、EIF2AK1、EIF2AK2、EIF2AK3、EIF2AK4、EIF2B1、EIF2B2、EIF2B3、EIF2B4、EIF2B5、EIF2D、EIF2S1、EIF2S2、EIF2S3、EIF3A、E IF3B、EIF3C、EIF3CL、EIF3D、EIF3E、EIF3F、EIF3G、EIF3H、EIF3I、EIF3J、EIF3K、EIF3L、EIF3M、EIF4A1、EIF4A2、EIF4A3、EIF4 B、EIF4E、EIF4E1B、EIF4E2、EIF4E3、EIF4EBP1、EIF4EBP2、EIF4EBP3、EIF4ENIF1、EIF4G1、EIF4G2、EIF4G3、EIF4H、EIF5、EIF5 A、EIF5A2、EIF5AL1、EIF5B、EIF6、EIPR1、ELAC1、ELAC2、ELANE、ELAVL1、ELAVL2、ELAVL3、ELAVL4、ELF1、ELF2、ELF3、ELF4、ELF 5、ELFN1、ELFN2、ELK1、ELK3、ELK4、ELL、ELL2、ELL3、ELMO1、ELMO2、ELMO3、ELMOD1、ELMOD2、ELMOD3、ELMSAN1、ELN、ELOA、ELOA2 、ELOA3、ELOA3B、ELOA3C、ELOA3D、ELOB、ELOC、ELOF1、ELOVL1、ELOVL2、ELOV L3、ELOVL4、ELOVL5、ELOVL6、ELOVL7、ELP1、ELP2、ELP3、ELP4、ELP5、ELP6、E LSPBP1、EMB、EMC1、EMC10、EMC2、EMC3、EMC4、EMC6、EMC7、EMC8、EMC9、EMCN、 EMD、EME1、EME2、EMG1、EMID1、EMILIN1、EMILIN2、EMILIN3、EML1、EML2、EML3 、EML4、EML5、EML6、EMP1、EMP2、EMP3、EMSY、EMX1、EMX2、EN1、EN2、ENAH、ENA M、ENC1、ENDOD1、ENDOG、ENDOU、ENDOV、ENG、ENGASE、ENHO、ENKD1、ENKUR、EN O1、ENO2、ENO3、ENO4、ENOPH1、ENOSF1、ENOX1、ENOX2、ENPEP、ENPP1、ENPP2、 ENPP3、ENPP4、ENPP5、ENPP6、ENPP7、ENSA、ENTHD1、ENTPD1、ENTPD2、ENTPD3、 ENTPD4、ENTPD5、ENTPD6、ENTPD7、ENTPD8、ENY2、EOGT、EOMES、EP300、EP400 、EPAS1、EPB41、EPB41L1、EPB41L2、EPB41L3、EPB41L4A、EPB41L4B、EPB41L5 、EPB42、EPC1、EPC2、EPCAM、EPDR1、EPG5、EPGN、EPHA1、EPHA10、EPHA2、EPHA 3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、EPHB6、E PHX1、EPHX2、EPHX3、EPHX4、EPM2A、EPM2AIP1、EPN1、EPN2、EPN3、EPO、EPOP、 EPOR, EPPIN, EPPIN-WFDC6, EPPK1, EPRS, EPS15, EPS15L1, EPS8, EPS8L1, EPS 8L2、EPS8L3、EPSTI1、EPX、EPYC、EQTN、ERAL1、ERAP1、ERAP2、ERAS、ERBB2、E RBB3、ERBB4、ERBIN、ERC1、ERC2、ERCC1、ERCC2、ERCC3、ERCC4、ERCC5、ERCC6、ERCC6L、ERCC6L2、ERCC8、EREG、ERF、 ERFE, ERG, ERG28, ERGIC1, ERGIC2, ERGIC3, ERH, ERI1, ERI2, ERI3, ERICH1, ERICH2, ERICH3, ERICH4, E RICH5、ERICH6、ERICH6B、ERLEC1、ERLIN1、ERLIN2、ERMAP、ERMARD、ERMN、ERMP1、ERN1、ERN2、ERO1A、ERO1 B, ERP27, ERP29, ERP44, ERRFI1, ERV3-1, ERVFRD-1, ERVMER34-1, ERVV-1, ERVV-2, ERVW-1, ESAM, ESCO1, ESCO2、ESD、ESF1、ESM1、ESPL1、ESPN、ESPNL、ESR1、ESR2、ESRP1、ESRP2、ESRRA、ESRRB、ESRRG、ESS2、ESX1 、ESYT1、ESYT2、ESYT3、ETAA1、ETDA、ETDB、ETDC、ETF1、ETFA、ETFB、ETFBKMT、ETFD H、ETFRF1、ETHE1、ETNK1、ETNK2、ETNPPL、ETS1、ETS2、ETV1、ETV2、ETV3、ETV3L、ETV 4、ETV5、ETV6、ETV7、EVA1A、EVA1B、EVA1C、EVC、EVC2、EVI2A、EVI2B、EVI5、EVI5L、 EVL、EVPL、EVPLL、EVX1、EVX2、EWSR1、EXD1、EXD2、EXD3、EXO1、EXO5、EXOC1、EXOC1L 、EXOC2、EXOC3、EXOC3L1、EXOC3L2、EXOC3L4、EXOC4、EXOC5、EXOC6、EXOC6 B、EXOC7、EXOC8、EXOG、EXOSC1、EXOSC10、EXOSC2、EXOSC3、EXOSC4、EXOSC5 、EXOSC6、EXOSC7、EXOSC8、EXOSC9、EXPH5、EXT1、EXT2、EXTL1、EXTL2、EXTL 3、EYA1、EYA2、EYA3、EYA4、EYS、EZH1、EZH2、EZR、F10、F11、F11R、F12、F13A 1, F13B, F2, F2R, F2RL1, F2RL2, F2RL3, F3, F5, F7, F8, F8A1, F8A2, F8A3, F9, FA2H, FAAH, FAAH2, FAAP100, FAAP20, FAAP24, FABP1, FABP12, FABP2, FAB P3, FABP4, FABP5, FABP6, FABP7, FABP9, FADD, FADS1, FADS2, FADS3, FADS6, FAF1, FAF2, FAH, FAHD1, FAHD2A, FAHD2B, FAIM, FAIM2, FAM102A, FAM102B 、FAM103A1、FAM104A、FAM104B、FAM105A、FAM106A、FAM107A、FAM107B、FA M109A、FAM109B、FAM110A、FAM110B、FAM110C、FAM110D、FAM111A、FAM111B 、FAM114A1、FAM114A2、FAM117A、FAM117B、FAM118A、FAM118B、FAM120A、FA M120AOS、FAM120B、FAM120C、FAM122A、FAM122B、FAM122C、FAM124A、FAM12 4B、FAM126A、FAM126B、FAM129A、FAM129B、FAM129C、FAM131A、FAM131B、FA M131C、FAM133A、FAM133B、FAM135A、FAM135B、FAM136A、FAM13A、FAM13B、F AM13C、FAM149A、FAM149B1、FAM151A、FAM151B、FAM153A、FAM153B、FAM153 C、FAM155A、FAM155B、FAM156A、FAM156B、FAM159A、FAM159B、FAM160A1、FA M160A2、FAM160B1、FAM160B2、FAM161A、FAM161B、FAM162A、FAM162B、FAM163A、FAM163B、FAM166A、FAM166B、FAM167A、FAM167B、FAM168A、FAM168B、FAM169A、FAM169B、FAM170A、FAM170B、FAM171A1、FAM171A2、FAM171B、FAM172A、FAM173A、FAM173B、FAM174A、FAM174B、FAM177A1、FAM177B、FAM178B、FAM180A、FAM180B、FAM181A、FAM181B、FAM182B、FAM183A、FAM184A、FAM184B、FAM185A、FAM186A、FAM186B、FAM187A、FAM187B、FAM189A1 FAM189A2, FAM189B, FAM192A, FAM193A, FAM193B, FAM196A, FAM196B, FAM198A, FAM198B, FAM199X, FAM19A1, FAM19A2, FAM19A3, FAM19A4, FAM19A5, FAM200A, FAM200B, FAM204A, FAM205A, FAM205C, FAM206A, FAM207A, FAM208A, FAM208B, FAM2 09A, FAM209B, FAM20A, FAM20B, FAM20C, FAM210A, FAM210B, FAM212A, FAM212B, FAM213A, FAM213B, FAM214A, FAM214B, FAM216A, FAM216B, FAM217A, FAM217B, FAM218A, FAM219A, FAM219B, FAM220A, FAM221A, FAM221B, FAM222A, FAM222B, FAM22 7A, FAM227B, FAM228A, FAM228B, FAM229A, FAM229B, FAM230A, FAM231A, FAM231B, FAM231C, FAM231D, FAM234A, FAM234B, FAM236A, FAM236B, FAM236C, FAM236D, FAM237A, FAM237B, FAM240A, FAM240B, FAM24A, FAM24B, FAM25A, FAM25C, FAM25G FAM26D, FAM26E, FAM26F, FAM32A, FAM35A, FAM3A, FAM3B, FAM3C, FAM3D, FAM43A, FAM43B, FAM45A, FAM46A, FAM46B, FAM46C, FAM46D, FAM47A, FAM47B, FAM47C, FAM47E, FAM47E-STBD1, FAM49A, FAM49B, FAM50A, FAM50B, FAM53A, FAM53B, FAM53C FAM57A, FAM57B, FAM58A, FAM60A, FAM69A, FAM69B, FAM69C, FAM71A, FAM71B, FAM71C, FAM71D, FAM71E1, FAM71E2, FAM71F1, FAM71F2, FAM72A, FAM72 B、FAM72C、FAM72D、FAM76A、FAM76B、FAM78A、FAM78B、FAM81A、FAM81B、FAM 83A、FAM83B、FAM83C、FAM83D、FAM83E、FAM83F、FAM83G、FAM83H、FAM84A、F AM84B、FAM86B1、FAM86B2、FAM86C1、FAM89A、FAM89B、FAM8A1、FAM90A1、F AM90A26、FAM91A1、FAM92A、FAM92B、FAM95C、FAM96A、FAM96B、FAM98A、FAM 98B、FAM98C、FAM9A、FAM9B、FAM9C、FAN1、FANCA、FANCB、FANCC、FANCD2、FA NCD2OS、FANCE、FANCF、FANCG、FANCI、FANCL、FANCM、FANK1、FAP、FAR1、FAR 2、FARP1、FARP2、FARS2、FARSA、FARSB、FAS、FASLG、FASN、FASTK、FASTKD1 、FASTKD2、FASTKD3、FASTKD5、FAT1、FAT2、FAT3、FAT4、FATE1、FAU、FAXC、F AXDC2、FBF1、FBL、FBLIM1、FBLL1、FBLN1、FBLN2、FBLN5、FBLN7、FBN1、FBN2 、FBN3、FBP1、FBP2、FBRS、FBRSL1、FBXL12、FBXL13、FBXL14、FBXL15、FBXL1 6、FBXL17、FBXL18、FBXL19、FBXL2、FBXL20、FBXL22、FBXL3、FBXL4、FBXL5 、FBXL6、FBXL7、FBXL8、FBXO10、FBXO11、FBXO15、FBXO16、FBXO17、FBXO18、 FBXO2、FBXO21、FBXO22、FBXO24、FBXO25、FBXO27、FBXO28、FBXO3、FBXO30、 FBXO31、FBXO32、FBXO33、FBXO34、FBXO36、FBXO38、FBXO39、FBXO4、FBXO40 , FBXO41, FBXO42, FBXO43, FBXO44, FBXO45, FBXO46, FBXO47, FBXO48, FBXO5, FBXO6, FBXO7, FBXO8, FBXO9, FBXW10, FBXW11, FBXW12, FBXW2, FBXW4, FBXW5, FBXW7, FBXW8, FBXW9, FCAMR, FCAR, FCER1A, FCER1G, FCER2, FCF1, FCGBP, FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A, FCGR3B, FCGRT, FCHO1, FCHO2, FCHSD1, FCHSD2, FCMR, FCN1 、FCN2、FCN3、FCRL1、FCRL2、FCRL3、FCRL4、FCRL5、FCRL6、FCRLA、FCRLB、FDCSP、FDFT1、FDPS、FDX1、FDX2、FDXACB1、FDXR、FE CH、FEM1A、FEM1B、FEM1C、FEN1、FER、FER1L5、FER1L6、FERD3L、FERMT1、FERMT2、FERMT3、FES、FETUB、FEV、FEZ1、FEZ2、FEZF1、 FEZF2、FFAR1、FFAR2、FFAR3、FFAR4、FGA、FGB、FGD1、FGD2、FGD3、FGD4、FGD5、FGD6、FGF1、FGF10、FGF11、FGF12、FGF13、FGF14 、FGF16、FGF17、FGF18、FGF19、FGF2、FGF20、FGF21、FGF22、FGF23、FGF3、FGF4、FGF5、FGF6、FGF7、FGF8、FGF9、FGFBP1、FGFBP2 FGFBP3, FGFR1, FGFR1OP, FGFR1OP2, FGFR2, FGFR3, FGFR4, FGFRL1, FGG, FGGY, FGL1, FGL2, F GR, FH, FHAD1, FHDC1, FHIT, FHL1, FHL2, FHL3, FHL5, FHOD1, FHOD3, FIBCD1, FIBIN, FIBP, FICD FIG4, FIGLA, FIGN, FIGNL1, FIGNL2, FILIP1, FILIP1L, FIP1L1, FIS1, FITM1, FITM2, FIZ1, FJ X1, FKBP10, FKBP11, FKBP14, FKBP15, FKBP1A, FKBP1B, FKBP1C, FKBP2, FKBP3, FKBP4, FKBP5, F KBP6, FKBP7, FKBP8, FKBP9, FKBPL, FKRP, FKTN, FLAD1, FLCN, FLG, FLG2, FLI1, FLII, FLNA, FLN B. FLNC, FLOT1, FLOT2, FLRT1, FLRT2, FLRT3, FLT1, FLT3, FLT3LG, FLT4, FLVCR1, FLVCR2, FLYW CH1, FLYWCH2, FMC1, FMN1, FMN2, FMNL1, FMNL2, FMNL3, FMO1, FMO2, FMO3, FMO4, FMO5, FMOD, FM R1, FMR1NB, FN1, FN3K, FN3KRP, FNBP1, FNBP1L, FNBP4, FNDC1, FNDC10, FNDC11, FNDC3A, FNDC3 B. FNDC4, FNDC5, FNDC7, FNDC8, FNDC9, FNIP1, FNIP2, FNTA, FN TB, FO681492.1, FO681542.1, FOCAD, FOLH1, FOLR1, FOLR2, FOL R3、FOPNL、FOS、FOSB、FOSL1、FOSL2、FOXA1、FOXA2、FOXA3、FOX B1, FOXB2, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3, FOXD4, FOXD4L1 、FOXD4L3、FOXD4L4、FOXD4L5、FOXD4L6、FOXE1、FOXE3、FOXF1、FOXF2、FOXG1、FOXH1、FOXI1、FOXI2、FOXI3、FOXJ1、FOXJ2、FOXJ3、FOXK1、FOXK2、FOXL1、FOXL2、FOXL2NB、FOX XM1、FOXN1、FOXN2、FOXN3、FOXN4、FOXO1、FOXO3、FOXO4、FOXO6、FOXP1、FOXP2、FOXP3、FOXP4、FOXQ1、FOXR1、FOXR2、FOXRED1、FOXRED2、FOXS1、FP236240.1、FP565260.1 P565260.2, FP565260.3, FP565260.4, FP565260.6, FP565260.7, FP565324.1, FP565324.2, FPGS, FPGT, FPGT-TNNI3K, FPR1, FPR2, FPR3, FRA10AC1, FRAS1, FRAT1, FRAT2, FREM1, FREM2, FREM3, FRG1, FRG2, FRG2B, FRG2C, FRK, FRMD1, FRMD3, FRMD4A, FRMD4B, FRMD5, FRMD6, FRMD7, FRMD8, FRMPD1, FRMPD2, FRMPD3, FRMPD4, FRRS1, FRRS1L, FRS2 、FRS3、FRY、FRYL、FRZB、FSBP、FSCB、FSCN1、FSCN2、FSCN3、FSD1、FSD1L、FSD2、FSHB、FSHR、FSIP1、FSIP2、FST、FSTL1、FSTL3、FSTL4、FSTL5、FTCD、FTCDNL1、FTH1、FTH L17、FTL、FTMT、FTO、FTSJ1、FTSJ3、FUBP1、FUBP3、FUCA1、FUCA2、FUK、FUNDC1、FUNDC2、FUOM、FURIN、FUS、FUT1、FUT10、FUT11、FUT2、FUT3、FUT4、FUT5、FUT6、FUT7、FUT 8、FUT9、FUZ、FXN、FXR1、FXR2、FXYD1、FXYD2、FXYD3、FXYD4、FXYD5、FXYD6、FXYD6-FXYD2、FXYD7、FYB1、FYB2、FYCO1、FYN、FYTTD1、FZD1、FZD10、FZD2、FZD3、FZD4 5. 、GABPA、GABPB1、GABPB2、GABRA1、GABRA2、GABRA3、GABRA4、GABRA5、GABRA6、GABRB1 、GABRB2、GABRB3、GABRD、GABRE、GABRG1、GABRG2、GABRG3、GABRP、GABRQ、GABRR1、GABRR2、GABRR3、GAD1、GAD2、GADD45A、GADD45B、GADD45G、GADD45GIP1、GADL1、GAGE1、G AGE10、GAGE12B、GAGE12C、GAGE12D、GAGE12E、GAGE12F、GAGE12G、GAGE12H、GAGE12J、GAGE13、GAGE2A、GAGE2E、GAK、GAL、GAL3ST1、GAL3ST2、GAL3ST3、GAL3ST4、GALC、GALE 、GALK1、GALK2、GALM、GALNS、GALNT1、GALNT10、GALNT11、GALNT12、GALNT13、GALNT 14、GALNT15、GALNT16、GALNT17、GALNT18、GALNT2、GALNT3、GALNT4、GALNT5、GALNT 6、GALNT7、GALNT8、GALNT9、GANLNTL5、GALTL6、GALP、GALR1、GALR2、GALR3、GALT、G AMT、GAN、GANAB、GANC、GAP43、GAPDH、GAPDHS、GAPT、GAPVD1、GAR1、GAREM1、GAREM2、 GARNL3、GARS、GART、GAS1、GAS2、GAS2L1、GAS2L2、GAS2L3、GAS6、GAS7、GAS8、GAST、 GATA1、GATA2、GATA3、GATA4、GATA5、GATA6、GATAD1、GATAD2A、GATAD2B、GATB、GATC、 GATD1、GATM、GATS、GBA、GBA2、GBA3、GBE1、GBF1、GBGT1、GBP1、GBP2、GBP3、GBP4、GB P5、GBP6、GBP7、GBX1、GBX2、GC、GCA、GCAT、GCC1、GCC2、GCDH、GCFC2、GCG、GCGR、GCH1 、GCHFR、GCK、GCKR、GCLC、GCLM、GCM1、GCM2、GCN1、GCNA、GCNT1、GCNT2、GCNT3、GCNT4、GCNT7、GCOM1、GC SAM、GCSAML、GCSH、GDA、GDAP1、GDAP1L1、GDAP2、GDE1、GDF1、GDF10、GDF11、GDF15、GDF2、GDF3、GDF5、GD F5OS、GDF6、GDF7、GDF9、GDI1、GDI2、GDNF、GDPD1、GDPD2、GDPD3、GDPD4" MIN4、GEMIN5、GEMIN6、GEMIN7、GEMIN8、GEN1、GET4、GFAP、GFER、GFI1、GFI1B、GFM1、GFM2、GFOD1、GFOD2 、GFPT1、GFPT2、GFRA1、GFRA2、GFRA3、GFRA4、GFRAL、GFY、GGA1、GGA2、GGA3、GGACT 、GGCT、GGCX、GGH、GGN、GGNBP2、GGPS1、GGT1、GGT2、GGT5、GGT6、GGT7、GGTLC1、GGTLC2、GGTLC 3、GH1、GH2、GHDC、GHITM、GHR、GHRH、GHRHR、GHRL、GHSR、GID4、GID8、GIF、GIGYF1、GIGYF2、GI MAP1、GIMAP1-GIMAP5、GIMAP2、GIMAP4、GIMAP5、GIMAP6、GIMAP7、GIMAP8、GIMD1、GIN1、GINM 1、GINS1、GINS2、GINS3、GINS4、GIP、GIPC1、GIPC2、GIPC3、GIPR、GIT1、GIT2、GJA1、GJA10、GJA 3、GJA4、GJA5、GJA8、GJA9、GJB1、GJB2、GJB3、GJB4、GJB5、GJB6、GJB7、GJC1、GJC2、GJC3、GJD2 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4-39、IGHV4-4、IGHV4-59、IGHV4-61、IGHV4OR15-8、IGHV5-51、IG HV6-1, IGHV7-81, IGIP, IGKC, IGKJ1, IGKJ2, IGKJ3, IGKJ4, IGKJ5 、IGKV1-12、IGKV1-16、IGKV1-17、IGKV1-27、IGKV1-33、IGKV1-37、IGKV1-39、IGKV1-5 、IGKV1-6、IGKV1-8、IGKV1-9、IGKV1D-12、IGKV1D-13、IGKV1D-16、IGKV1D-17、IGKV1D-33、IGKV1D-37、IGKV1D-39、IGKV1D-42、IGKV1D-43、IGKV1D-8、IGKV1OR2-108、IGKV2-24、IGKV2-28、IGKV2-30、IGKV2-40、IGKV2D-24、IGKV2D-26、IGKV2D-28、IGKV2D-29、IGKV2D-30、IGKV2D-40、IGKV3-11、IGKV3-15、IGKV3-20、IGKV3-7、IGKV3D-11、IGKV3D-15、IGKV3D-20、IGKV3D-7、IGKV3OR2-268、IGKV4-1、IGKV5-2、IGKV6-21、IGKV6D-21、IGKV6D-41、IGLC1、IGLC2、IGLC3、IGLC7、IGLJ1、IGLJ2、IGLJ3、IGLJ4、IGLJ5、IGLJ6、IGLJ7 、IGLL1、IGLL5、IGLON5、IGLV10-54、IGLV11-55、IGLV1-36、IGLV1-40、IGLV 1-44、IGLV1-47、IGLV1-50、IGLV1-51、IGLV2-11、IGLV2-14、IGLV2-18、IGL V2-23, ILV2-33, ILV2-8, ILV3-1, ILV3-10, ILV3-12, ILV3-16, ILV3-19, ILV3-21, ILV3-22, ILV3-25, ILV3-27, ILV3-32, ILV3-9, ILV4 -3、IGLV4-60、IGLV4-69、IGLV5-37、IGLV5-45、IGLV5-48、IGLV5-52、IGLV6 -57、IGLV7-43、IGLV7-46、IGLV8-61、IGLV9-49、IGSF1、IGSF10、IGSF11、IGS F21, IGSF22, IGSF23, IGSF3, IGSF5, IGSF6, IGSF8, IGSF9, IGSF9B, IHH, IK, IKBIP, IKBKB, IKBKE, IKBKG, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, IL10, IL10 RA、IL10RB、IL11、IL11RA、IL12A、IL12B、IL12RB1、IL12RB2、IL13、IL13RA1 、IL13RA2、IL15、IL15RA、IL16、IL17A、IL17B、IL17C、IL17D、IL17F、IL17RA 、IL17RB、IL17RC、IL17RD、IL17RE、IL17REL、IL18、IL18BP、IL18R1、IL18RA P、IL19、IL1A、IL1B、IL1F10、IL1R1、IL1R2、IL1RAP、IL1RAPL1、IL1RAPL2、IL 1RL1、IL1RL2、IL1RN、IL2、IL20、IL20RA、IL20RB、IL21、IL21R、IL22、IL22R A1、IL22RA2、IL23A、IL23R、IL24、IL25、IL26、IL27、IL27RA、IL2RA、IL2RB、I L2RG、IL3、IL31、IL31RA、IL32、IL33、IL34、IL36A、IL36B、IL36G、IL36RN、I L37、IL3RA、IL4、IL4I1、IL4R、IL5、IL5RA、IL6、IL6R、IL6ST、IL7、IL7R、IL9、IL9R, ILDR1, ILDR2, ILF2, ILF3, ILK, ILKAP, ILVBL, IMMP1L, IMMP2L, I MMT、IMP3、IMP4、IMPA1、IMPA2、IMPACT、IMPAD1、IMPDH1、IMPDH2、IMP、 G1、IMPG2、INA、INAFM1、INAFM2、INAVA、INCA1、INCENP、INF2、ING1、ING2、ING3、IN G4、ING5、INHA、INHBA、INHBB、INHBC、INHBE、INIP、INMT、INMT-MINDY4、INO80、INO8 0B、INO80B-WBP1、INO80C、INO80D、INO80E、INPP1、INPP4A、INPP4B、INPP5A、INPP5B INPP5D、INPP5E、INPP5F、INPP5J、INPP5K、INPPL1、INS、INSC、INSIG1、INSIG2、INS -IGF2、INSL3、INSL4、INSL5、INSL6、INSM1、INSM2、INSR、INSRR、INTS1、INTS10、IN TS11、INTS12、INTS13、INTS14、INTS2、INTS3、INTS4、INTS5、INTS6、INTS6L、INTS7、 INTS8、INTS9、INTU、INVS、IP6K1、IP6K2、IP6K3、IPCEF1、IPMK、IPO11、IPO13、IPO4、 IPO5、IPO7、IPO8、IPO9、IPP、IPPK、IQANK1、IQCA1、IQCA1L、IQCB1、IQCC、IQCD、IQCE 、IQCF1、IQCF2、IQCF3、IQCF5、IQCF6、IQCG、IQCH、IQCJ、IQCJ-SCHIP1、IQCK、IQCM、 IQGAP1、IQGAP2、IQGAP3、IQSEC1、IQSEC2、IQSEC3、IQUB、IREB2、IRF1、IRF2、IRF2B P1, IRF2BP2, IRF2BPL, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, IRF9, IRGC, IRGM, IRGQ 、IRS1、IRS2、IRS4、IRX1、IRX2、IRX3、IRX4、IRX5、IRX6、ISCA1、ISCA2、ISCU、ISG15 、ISG20、ISG20L2、ISL1、ISL2、ISLR、ISLR2、ISM1、ISM2、ISOC1、ISOC2、ISPD、IST1 ISX, ISY1, ISY1-RAB43, ISYNA1, ITCH, ITFG1, ITFG2, ITGA1, ITGA10, ITGA11, ITG A2、ITGA2B、ITGA3、ITGA4、ITGA5、ITGA6、ITGA7、ITGA8、ITGA9、ITGAD、ITGAE、ITGAL 、ITGAM、ITGAV、ITGAX、ITGB1、ITGB1BP1、ITGB1BP2、ITGB2、ITGB3、ITGB3BP、ITGB4 ITGB5, ITGB6, ITGB7, ITGB8, ITGBL1, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, I TK、ITLN1、ITLN2、ITM2A、ITM2B、ITM2C、ITPA、ITPK1、ITPKA、ITPKB、ITPKC、ITPR1、I TPR2、ITPR3、ITPRIP、ITPRIPL1、ITPRIPL2、ITSN1、ITSN2、IVD、IVL、IVNS1ABP、IWS1 、IYD、IZUMO1、IZUMO1R、IZUMO2、IZUMO3、IZUMO4、JADE1、JADE2、JADE3、JAG1、JAG2 、JAGN1、JAK1、JAK2、JAK3、JAKMIP1、JAKMIP2、JAKMIP3、JAM2、JAM3、JAML、JARID2、JAZF 1、JCAD、JCHAIN、JDP2、JKAMP、JMJD1C、JMJD4、JMJD6、JMJD7、JMJD7-PLA2G4B、JMJD8、JM Y, JOSD1, JPH2, JPH3, JPH4, JPT1, JPT2, JRK, JRKL, JSRP1, JTB, JUN, JUNB. JUND、JUP、KAAG1、KALRN、KANK1、KANK2、KANK3、KANK4、KANSL1、KANSL1L、KANSL2、KANSL3 、KANTR、KARS、KAT14、KAT2A、KAT2B、KAT5、KAT6A、KAT6B、KAT7、KAT8、KATNA1、KATNAL1、KATNAL2、KATNB1、KATNBL1、KAZALD1、KAZN、KBTBD11、KBTBD11-OT1、KBTBD12、KBTBD13、KBTBD2、KBTBD3、KBTBD4、KBTBD6 BTBD7、KBTBD8、KCMF1、KCNA1、KCNA10、KCNA2、KCNA3、KCNA4、KCNA5、KCNA7、KCNAB1、KCNAB2、KCNAB3、KCNB1、KCNB2、KCNC1、KCNC2、KCNC3、KCNC4、KCND1、KCND2、KCND3、KCNE1、KCNE1B、KCNE2、KCNE3、KCNE4、KCNE5 、KCNF1、KCNG1、KCNG2、KCNG3、KCNG4、KCNH1、KCNH2、KCNH3、KCNH4、KCNH5、KCNH6、KCNH7、KCNH8、KCNIP1、KCNIP2、KCNIP3、KCN IP4、KCNJ1、KCNJ10、KCNJ11、KCNJ12、KCNJ13、KCNJ14、KCNJ15、KCNJ16、KCNJ18、KCNJ2、KCNJ3、KCNJ4、KCNJ5、KCNJ6、KCNJ8、KCNJ NJ9、KCNK1、KCNK10、KCNK12、KCNK13、KCNK15、KCNK16、KCNK17、KCNK18、KCNK2、KCNK3、KCNK4、KCNK5、KCNK6、KCNK7、KCNK9、KCNK NMA1、KCNMB1、KCNMB2、KCNMB3、KCNMB4、KCNN1、KCNN2、KCNN3、KCNN4、KCNQ1、KCNQ2、KCNQ3、KCNQ4、KCNQ5、KCNRG、KCNS1、KCNS2 、KCNS3、KCNT1、KCNT2、KCNU1、KCNV1、KCNV2、KCP、KCTD1、KCTD10、KCTD11、KCTD12、KCTD13、KCTD14、KCTD15、KCTD16、KCTD17、KCTD18、KCTD19、KCTD2、 KCTD20、KCTD21、KCTD3、KCTD4、KCTD5、KCTD6、KCTD7、KCTD8、KCTD9、KDELC1、KDELC2、KDELR1、KDELR2、KDELR3、KDF1、KDM1A、KDM1B、KDM2A、KDM2B、KDM 3A、KDM3B、KDM4A、KDM4B、KDM4C、KDM4D、KDM4E、KDM4F、KDM5A、KDM5B、KDM5C、KDM5D、KDM6A、KDM6B、KDM7A、KDM8、KDR、KDSR、KEAP1、KEL、KERA、KF45957 0.1、KHDC1、KHDC1L、KHDC3L、KHDRBS1、KHDRBS2、KHDRBS3、KHK、KHNYN、KHSRP、KIAA0040、KIAA0100、KIAA0141、KIAA0232、KIAA0319、KIAA0319L、KIAA0 355、KIAA0368、KIAA0391、KIAA0408、KIAA0513、KIAA0556、KIAA0586、KIAA0753、KIAA0825、KIAA0895、KIAA0895L、KIAA0907、KIAA0930、KIAA1024、KIAA0907 IAA1024L、KIAA1107、KIAA1109、KIAA1143、KIAA1147、KIAA1161、KIAA1191、KIAA1210、KIAA1211、KIAA1211L、KIAA1217、KIAA1257、KIAA1324、KIAA13 24L, KIAA1328, KIAA1456, KIAA1468, KIAA1522, KIAA1524, KIAA1549, KIAA1549L, KIAA1551, KIAA1586, KIAA1614, KIAA1644, KIAA1671, KIAA1683, KIAA1755, KIAA1841, KIAA1958, KIAA2012, KIAA2013, KIAA2026, KIDINS220, KIF11, KIF12, KIF13A, KIF13B, KIF14, KIF15, KIF16B, KIF17, KIF18A, KIF 18B, KIF19, KIF1A, KIF1B, KIF1BP, KIF1C, KIF20A, KIF20B, KIF21A, KIF21B, KIF22, KIF23, KIF24, KIF25, KIF26A, KIF26B, KIF27, KIF2A, KIF2B, KIF2C, KIF3A, KIF3B, KIF3C, KIF4A, KIF4B, KIF5A, KIF5B, KIF5C, KIF6, KIF7, KIF9, KIFAP3, KIFC1, KIFC2 KIFC3, KIN, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DP1, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL2, KIR3DL3, KIR3DP1, KIR3DS1, KIR3DX1, KIRREL1, KIRREL2, KIRREL3, KISS1, KISS1R, KIT, KITLG, KIZ, KL 、KLB、KLC1、KLC2、KLC3、KLC4、KLF1、KLF10、KLF11、KLF12、KLF13、KLF14、 KLF15、KLF16、KLF17、KLF18、KLF2、KLF3、KLF4、KLF5、KLF6、KLF7、KLF8、K LF9、KLHDC1、KLHDC10、KLHDC2、KLHDC3、KLHDC4、KLHDC7A、KLHDC7B、KLHD C8A、KLHDC8B、KLHDC9、KLHL1、KLHL10、KLHL11、KLHL12、KLHL13、KLHL14、K LHL15, KLHL17, KLHL18, KLHL2, KLHL20, KLHL21, KLHL22, KLHL23, KLHL24, KLHL25, KLHL26, KLHL28, KLHL29, KLHL3, KLHL30, KLHL31, KLHL32, KLHL3 3、KLHL34、KLHL35、KLHL36、KLHL38、KLHL4、KLHL40、KLHL41、KLHL42、KLH L5、KLHL6、KLHL7、KLHL8、KLHL9、KLK1、KLK10、KLK11、KLK12、KLK13、KLK14 、KLK15、KLK2、KLK3、KLK4、KLK5、KLK6、KLK7、KLK8、KLK9、KLKB1、KLLN、KLRB1、KLRC1 、KLRC2、KLRC3、KLRC4、KLRC4-KLRK1、KLRD1、KLRF1、KLRF2、KLRG1、KLRG2、KLRK1、KMO 、KMT2A、KMT2B、KMT2C、KMT2D、KMT2E、KMT5A、KMT5B、KMT5C、KNCN、KNDC1、KNG1、KNL1 、BUTTON1、KNSTRN、KNTC1、KP420437.1、KP420437.2、KP420437.3、KP420439.1、KP4204 40.1、KP420440.2、KP420440.3、KP420440.4、KP420440.5、KP420440.6、KP420440. 7、KP420440.8、KP420440.9、KP420441.1、KP420441.2、KP420441.3、KP420441.4、KP 420441.5、KP420442.2、KP420442.3、KP420443.1、KP420444.1、KP420444.2、KP420 444.3、KP420444.4、KP420444.5、KP420444.6、KP420444.7、KP420446.1、KP420446.2、KPNA1、KPNA2、KPNA3、KPNA4、KPNA5、KPNA6、KPNA7、KPNB1、KPRP、KPTN、KRAS、KRBA1、KRBA2、KRBOX1、KRBOX 4、KRCC1、KREMEN1、KREMEN2、KRI1、KRIT1、KRR1、KRT1、KRT10、KRT12、KRT13、KRT14、KRT15、KRT16、KRT17、KR T18、KRT19、KRT2、KRT20、KRT222、KRT23、KRT24、KRT25、KRT26、KRT27、KRT28、KRT3、KRT31、KRT32、KRT33A、K RT33B、KRT34、KRT35、KRT36、KRT37、KRT38、KRT39、KRT4、KRT40、KRT5、KRT6A、KRT6B、KRT6C、KRT7、KRT71、KR T72、KRT73、KRT74、KRT75、KRT76、KRT77、KRT78、KRT79、KRT8、KRT80、KRT81、KRT82、KRT83、KRT84、KRT85、KR T86、KRT9、KRTAP10-1、KRTAP10-10、KRTAP10-11、KRTAP10-12、KRTAP10-2、KRTAP10-3、KRTAP10-4、KRTAP10 -5、KRTAP10-6、KRTAP10-7、KRTAP10-8、KRTAP10-9、KRTAP1-1、KRTAP11-1、KRTAP12-1、KRTAP12-2、KRTAP12 -3、KRTAP12-4、KRTAP1-3、KRTAP13-1、KRTAP13-2、KRTAP13-3、KRTAP13-4、KRTAP1-4、KRTAP1-5、KRTAP15-1. 、KRTAP16-1、KRTAP17-1、KRTAP19-1、KRTAP19-2、KRTAP19-3、KRTAP19-4、KRTAP19-5、KRTAP19-6、KRTAP19-7、KRTAP19-8、KRTAP20 -1、KRTAP20-2、KRTAP20-3、KRTAP20-4、KRTAP2-1、KRTAP21-1、KRTAP21-2、KRTAP21-3、KRTAP2-2、KRTAP22-1、KRTAP22-2、KRTAP2-3 、KRTAP23-1、KRTAP2-4、KRTAP24-1、KRTAP25-1、KRTAP26-1、KRTAP27-1、KRTAP29-1、KRTAP3-1、KRTAP3-2、KRTAP3-3、KRTAP4-1、KRTAP4-11、KRTAP4-12、KRTAP4-16、KRTAP4-2 、KRTAP4-3、KRTAP4-4、KRTAP4-5、KRTAP4-6、KRTAP4-7、KRTAP4-8、KRTAP4-9、KRTAP5-1、KRTAP5-10、KRTAP5 -11、KRTAP5-2、KRTAP5-3、KRTAP5-4、KRTAP5-5、KRTAP5-6、KRTAP5-7、KRTAP5-8、KRTAP5-9、KRTAP6-1、KRTAP 6-2、KRTAP6-3、KRTAP7-1、KRTAP8-1、KRTAP9-1、KRTAP9-2、KRTAP9-3、KRTAP9-4、KRTAP9-6、KRTAP9-7、KRTA P9-8、KRTAP9-9、KRTCAP2、KRTCAP3、KRTDAP、KSR1、KSR2、KTI12、KTN1、KU645196.1、KU645196.2、KU645196.3 、KU645196.4、KU645196.5、KU645196.6、KU645196.7、KU645196.8、KU645196.9、KU645197.1、KU645197.2 、KU645197.3、KU645197.4、KU645197.5、KU645198.1、KXD1、KY、KYAT1、KYAT3、KYNU、L1CAM、L1TD1、L2HGDH 、L34079.1、L3HYPDH、L3MBTL1、L3MBTL2、L3MBTL3、L3MBTL4、LACC1、LACRT、LACTB、LACTB2、LACTBL1、LAD1、LAG3、LAGE3、LAIR1、LAIR2、LALBA、LAMA1、LAMA2、LAMA4、LAMA5、LAMB1、LAMB1 、LAMC2、LAMC3、LAMP1、LAMP2、LAMP3、LAMP5、LAMTOR1、LAMTOR2、LAMTOR3、LAMTOR4、LAMTOR5、LANCL1、LANCL2、LANCL3、LAP3、LAPTM4A、LAPTM4B、LAPTM5、LARGE1、LARGE2 、LARP1、LARP1B、LARP4、LARP4B、LARP6、LARP7、LARS、LARS2、LAS1L、LASP1、LAT、L AT2、LATS1、LATS2、LAX1、LAYN、LBH、LBHD1、LBP、LBR、LBX1、LBX2、LCA5、LCA5L、LCA T、LCE1A、LCE1B、LCE1C、LCE1D、LCE1E、LCE1F、LCE2A、LCE2B、LCE2C、LCE2D、LCE3A、LCE3B、LCE3C、LCE3D、LCE3E、LCE4A、LCE5A、LCE6A、LCK、LCLAT1、LCMT1、LCMT2、LCN1、LCN10、LCN12、LCN15、LCN2、LCN6、LCN8、LCN9、LCNL1、LCOR、LCORL、LCP1、LCP2、LCT、LCTL、LDAH、LDB1、LDB2、LDB3、LDHA、LDHAL6A、LDHAL6B、LDHB、LDHC、LDHD、LDLR、LDLRAD1、LDLRAD2、LDLRAD3、LDLRAD4、LDLRAP1、LDOC1、LEAP2、LECT2、LEF1、LEFTY1、LEFTY2、LEKR1、LELP1、LEMD1、LEMD2、LEMD3、LENEP、LENG1、LENG8、LENG9、LEO1、LEP、LEPR、LEPROT、LEPROTL1、LETM1、LETM2、LETMD1、LEUTX、LEXM、LFNG、LGALS1、LGALS12、LGALS13、LGALS14、LGALS16、LGALS2、LGALS3、LGALS3BP、LGALS4、LGALS7、LGALS7B、LGALS8、LGALS9、LGALS9B、LGALS9C、LGALSL、LGI1、LGI2、LGI3、LGI4、LGMN、LGR4、LGR5、LGR6、LGSN、LHB、LHCGR、LHFPL1、LHFPL2、LHFPL3、LHFPL4、LHFPL5、LHFPL6、LHPP、LHX1、LHX2、LHX3、LHX4、LHX5、LHX6、LHX8、LHX9、LIAS、LIF、LIFR、LIG1、LIG3、LIG4、LILRA1、LILRA2、LILRA3、LILRA4、LILRA5、LILRA6、LILRB1、LILRB2、LILRB3 、LILRB4、LILRB5、LIM2、LIMA1、LIMCH1、LIMD1、LIMD2、LIME1、LIMK1、LIMK2、LIMS1 、LIMS2、LIMS3、LIMS4、LIN28A、LIN28B、LIN37、LIN52、LIN54、LIN7A、LIN7B、LIN7C ,LIN9, LINC00094, LINC00116, LINC00282, LINC00672, LINC00675, LINC00694, LINC00854, LINC00890, LINC00959, LINC01125, LINC01556, LINC02210-CRHR1, LINGO1, LINGO2, LINGO3, LINGO4, LINS1, LIPA, LIPC, LIPE, LIPF, LIPG, LIPH, LIPI, LIPJ, LIPK, LIPM, LIPN, LIPT1, LIPT2, LITAF, LIX1, LIX1L, LKAAEAR1, LLGL1, LLGL2, LLPH, LMAN1, LMAN1L, LMAN2, LMAN2L, LMBR1, LMBR1L, LMBRD1, LMBRD2, LMCD1, LMF1, LMF2, LMLN 、LMNA、LMNB1、LMNB2、LMNTD1、LMNTD2、LMO1、LMO2、LMO3、LMO4、LMO7、LMO7DN、LMOD1、LMOD2、LMOD3、LMTK2、LMTK3、LMX1A、LMX1B、LNP1、LNPEP、LNPK、LNX1、LNX2、LO000005.1、LONP1、LONP2、LONRF1、LONRF2、LONRF3、LOR、LOX、LOXHD1、LOXL1、LOXL2、LOXL3、LOXL4、LPA、LPAR1、LPAR2、LPAR3、LPAR4、LPAR5、LPAR6、LPCAT1、LPCAT2、LPCAT3、LPCAT4、LPGAT1、LPIN1、LPIN2、LPIN3、LPL、LPO、LPP、LPXN、LRAT、LRBA、LRCH1、LRCH2、LRCH3、LRCH4、LRCOL1、LRFN1、LRFN2、LRFN3、LRFN4、LRFN5、LRG1、LRGUK、LRIF1、LRIG1、LRIG2、LRIG3、LRIT1、LRIT2、LRIT3、LRMDA、LRMP、LRP1、LRP10、LRP11、LRP12、LRP1B、LRP2、LRP2BP、LRP3、LRP4、LRP5、LRP5L、LRP6、LRP8、LRPAP1、LRPPRC、LRR1、LRRC1、LRRC10、LRRC10B、LRRC14、LRRC14B、LRRC15、LRRC17、LRRC18、LRRC19、LRRC2、LRRC20、LRRC23、LRRC24、LRRC25、LRRC26、LRRC27、LRRC28、LRRC29、LRRC3、LRRC30、LRRC31、LRRC32、LRRC34、LRRC36、LRRC37A、LRRC37A2、LRRC37A3、LRRC37B、LRRC38、LRRC39、LRRC3B、LRRC3C、LRRC4、LRRC40、LRRC41、LRRC42、LRRC43、LRRC45、LRRC46、LRRC47、LRRC49、LRRC4B、LRRC4C、LRRC52、LRRC53、LRRC55、LRRC56、LRRC57、LRRC58、LRRC59、LRRC6、LRRC61、LRRC63、LRRC66、LRRC69、LRRC7、LRRC70、LRRC71、LRRC72、LRRC73、LRRC74A、LRRC74B、LRRC75A、LRRC75B、LRRC8A、LRRC8B、LRRC8C、LRRC8D、LRRC8E、LRRC9、LRRCC1、LRRD1、LRRFIP1、LRRFIP2、LRRIQ1、LRRIQ 3、LRRIQ4、LRRK1、LRRK2、LRRN1、LRRN2、LRRN3、LRRN4、LRRN4CL、LRRTM1、LRRTM2、LRRTM3、LRRTM4、LRSAM1、LRT M1、LRTM2、LRTOMT、LRWD1、LSAMP、LSG1、LSM1、LSM10、LSM11、LSM12、LSM14A、LSM14B、LSM2、LSM3、LSM4、LSM5、L SM6、LSM7、LSM8、LSMEM1、LSMEM2、LSP1、LSR、LSS、LST1、LTA、LTA4H、LTB、LTB4R、LTB4R2、LTBP1、LTBP2、LTBP3、 LTBP4、LTBR、LTC4S、LTF、LTK、LTN1、LTV1、LUC7L、LUC7L2、LUC7L3、LUM、LURAP1、LURAP1L、LUZP1、LUZP2、LUZP 4、LUZP6、LVRN、LXN、LY6D、LY6E、LY6G5B、LY6G5C、LY6G6C、LY6G6D、LY6G6E、LY6G6F、LY6H、LY6K、LY6L、LY75、LY 75-CD302、LY86、LY9、LY96、LYAR、LYG1、LYG2、LYL1、LYN、LYNX1、LYPD1、LYPD2、LYPD3、LYPD4、LYPD5、LYPD6、LY PD6B、LYPD8、LYPLA1、LYPLA2、LYPLAL1、LYRM1、LYRM2、LYRM4、LYRM7、LYRM9、LYSMD1、LYSMD2、LYSMD3、LYSMD4、 、LYST、LYVE1、LYZ、LYZL1、LYZL2、LYZL4、LYZL6、LZIC、LZTFL1 、LZTR1、LZTS1、LZTS2、LZTS3、M1AP、M6PR、MAATS1、MAB21L1、MA B21L2、MAB21L3、MACC1、MACF1、MACROD1、MACROD2、MAD1L1、MAD2L1、MAD2L1BP、MAD2L2、MADCAM1、MADD、MAEA、MAEL、MAF、MAF1 MAGE、MAFB、MAFF、MAFG、MAFK、MAG、MAGEA1、MAGEA10、MAGEA11、MAGEA12、MAGEA2、MAGEA2B、MAGEA3、MAGEA4、MAGEA4、MAGEA4、MAGEA4 MAGEB1、MAGEB10、MAGEB16、MAGEB17、MAGEB18、MAGEB2、MAGEB3、MAGEB4、MAGEB5、MAGEB6EC1、MAGEB6P1 MAGEC2. MAGEL2、MAGI1、MAGI2、MAGI3、MAGIX、MAGOH、MAGOHB、MAGT1、MAIP1、MAJIN、MAK、MAK16、MAL MAL2、MALL、MALRD1、MALSU1、MALT1、MAMDC2、MAMDC4、MAML1、MAML2、MAML3、MAMLD1、MAMSTR、 MAN1A1、MAN1A2、MAN1B1、MAN1C1、MAN2A1、MAN2A2、MAN2B1、MAN2B2、MAN2C1、MANBA、MANBAL、MANEA、MANEAL、MANF、MANSC1、MANSC4、MAOA、MAOB、MAP10、MAP1A、MAP1B、MAP1LC3A、MAP1LC3B、MAP1LC3B2、MAP1LC3C、MAP1S、MAP2、MAP2K1、MAP2K2、MAP2K3、MAP2K4、MAP2K5、MAP2K6、MAP2K7、MAP3K1、MAP3K10、MAP3K11、MAP3K12、MAP3K13、MAP3K14、MAP3K15、MAP3K19、MAP3K2、MAP3K20、MAP3K21、MAP3K3、MAP3K4、MAP3K5、MAP3K6、MAP3K7、MAP3K7CL、MAP3K8、MAP3K9、MAP4、MAP4K1、MAP4K2、MAP4K3、MAP4K4、MAP4K5、MAP6、MAP6D1、MAP7、MAP7D1、MAP7D2、MAP7D3、MAP9、MAPK1、MAPK10、MAPK11、MAPK12、MAPK13、MAPK14、MAPK15、MAPK1IP1L、MAPK3、MAPK4、MAPK6、MAPK7、MAPK8、MAPK8IP1、MAPK8IP2、MAPK8IP3、MAPK9、MAPKAP1、MAPKAPK2、MAPKAPK3、MAPKAPK5、MAPKBP1、MAPRE1、MAPRE2、MAPRE3、MAPT、MARC1、MARC2、MARCH1、MARCH10、MARCH11、MARCH2、MARCH3、MARCH4、MARCH5、MARCH6、MARCH7、MARCH8、MARCH9、MARCKS、MARCKSL1、MARCO、MARF1、MARK1、MARK2、MARK3、MARK4、MARS、MARS2、MARVELD1、MARVELD2、MARVELD3、MAS1、MAS1L、MASP1、MASP2、MAST1、MAST2、MAST3、MAST4、MASTL、MAT1A、MAT2A、MAT2B、MATK、MATN1、MATN2、MATN3、MATN4、MATR3、MAU2、MAVS、MAX、MAZ、MB、MB21D1、MB21D2、MBD1 、MBD2、MBD3、MBD3L1、MBD3L2、MBD3L2B、MBD3L3、MBD3L4、MBD3L5、MBD4、MBD5、MBD6 、MBIP、MBL2、MBLAC1、MBLAC2、MBNL1、MBNL2、MBNL3、MBOAT1、MBOAT2、MBOAT4、MBOAT7、MBP、MBTD1、MBTPS1、MBTPS 2, MC1R, MC2R, MC3R, MC4R, MC5R, MCAM, MCAT, MCC, MCCC1, MCCC2, MCCD1, MCEE, MCEMP1, MCF2, MCF2L, MCF2L2, MCFD2 MCHR1, MCHR2, MCIDAS, MCL1, MCM10, MCM2, MCM3AP, MCM4, MCM5, MCM6, MCM7, MCM8, MCM9, MCMBP, MCMDC2, MC OLN1, MCOLN2, MCOLN3, MCPH1, MCRIP1, MCRIP2, MCRS1, MCTP1, MCTP2, MCTS1, MCU, MCUB, MCUR1, MDC1, MDFI, MDFIC. MDFIC2, MDGA1, MDGA2, MDH1, MDH1B, MDH2, MDK, MDM1, MDM2, MDM4, MDN1, MDP1, MDS2, ME1, ME2, ME3, MEA1, MEAF6.M ECOM, MECP2, MECR, MED1, MED10, MED11, MED12, MED12L, MED13, MED13L, MED14, MED14OS, MED15, MED16, MED17, MED 18. MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28, MED29, MED30, MED31, MED4, MED6, MED 7. MED8, MED9, MEDAG, MEF2A, MEF2B, MEF2C, MEF2D, MEFV, MEGF10, MEGF11, MEGF6, MEGF8, MEGF9, MEI1, MEI4, MEIG1 、MEIKIN、MEIOB、MEIOC、MEIS1、MEIS2、MEIS3、MELK、MELTF、MEMO1、MEN1、ME OX1、MEOX2、MEP1A、MEP1B、MEPCE、MEPE、MERTK、MESD、MESP1、MESP2、MEST、ME T、METAP1、METAP1D、METAP2、METRN、METRNL、METTL1、METTL11B、METTL12、M ETTL13、METTL14、METTL15、METTL16、METTL17、METTL18、METTL21A、METTL21 C、METTL22、METTL23、METTL24、METTL25、METTL26、METTL27、METTL2A、METT L2B、METTL3、METTL4、METTL5、METTL6、METTL7A、METTL7B、METTL8、METTL9、M EX3A、MEX3B、MEX3C、MEX3D、MFAP1、MFAP2、MFAP3、MFAP3L、MFAP4、MFAP5、MF F、MFGE8、MFHAS1、MFN1、MFN2、MFNG、MFRP、MFSD1、MFSD10、MFSD11、MFSD12、M FSD13A、MFSD14A、MFSD14B、MFSD14C、MFSD2A、MFSD2B、MFSD3、MFSD4A、MFSD 4B、MFSD5、MFSD6、MFSD6L、MFSD7、MFSD8、MFSD9、MGA、MGAM、MGAM2、MGARP、MG AT1、MGAT2、MGAT3、MGAT4A、MGAT4B、MGAT4C、MGAT4D、MGAT5、MGAT5B、MGEA5 、MGLL、MGME1、MGMT、MGP、MGRN1、MGST1、MGST2、MGST3、MIA、MIA3、MIA-RAB4B 、MIB1、MIB2、MICA、MICAL1、MICAL2、MICAL3、MICALCL、MICALL1、MICALL2、M ICB、MICU1、MICU2、MICU3、MID1、MID1IP1、MID2、MIDN、MIEF1、MIEF2、MIEN1、 MIER1、MIER2、MIER3、MIF、MIF4GD、MIGA1、MIGA2、MIIP、MILR1、MINDY1、MIN DY2、MINDY3、MINDY4、MINDY4B、MINK1、MINOS1、MINOS1-NBL1、MINPP1、MIOS、MIOX、MIP、MIPEP、MIPOL1、MIS12、MIS18A、MIS18BP1、MISP、MISP3、MITD1、MITF、MIXL1、MKI67、MKKS、MKL1、MKL2、MK LN1、MKNK1、MKNK2、MKRN1、MKRN2、MKRN2OS、MKRN3、MKS1、MKX、MLANA、MLC1、MLEC、MLF1、MLF2、MLH1、MLH3、MLIP、MLK L, MLLT1, MLLT10, MLLT11, MLLT3, MLLT6, MLN, MLNR, MLPH, MLST8, MLX, MLXIP, MLXIPL, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MMD, MMD2, MME, MMEL1, MMGT1, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP2 MMP20, MMP21, MMP23B, MMP24, MMP24-AS1, MMP25, MMP26, MMP27, MMP28, MMP3, MMP7, MMP8, MMP9, MMRN1, MMRN2, MMS19, MMS22L, MN1, MNAT1, MND1, MNDA, MNS1, MNT, MNX1, MOAP1, MOB1A, MOB1B, MOB2, MOB3A, MOB 3B、MOB3C、MOB4、MOBP、MOCOS、MOCS1、MOCS2、MOCS3、MOG、MOGAT1、MOGAT2、MOGAT3、MOGS、MOK、MON1A、MO N1B、MON2、MORC1、MORC2、MORC3、MORC4、MORF4L1、MORF4L2、MORN1、MORN2、MORN3、MORN4、MORN5、MOS、MOS PD1、MOSPD2、MOSPD3、MOV10、MOV10L1、MOXD1、MPC1、MPC1L、MPC2、MPDU1、MPDZ、MPEG1、MPG、MPHOSPH10、 MPHOSPH6、MPHOSPH8、MPHOSPH9、MPI、MPIG6B、MPL、MPLKIP、MPND、MPO、MPP1、MPP2、MPP3、MPP4、MPP5、MPP 6, MPP7, MPPE1, MPPED1, MPPED2, MPRIP, MPST, MPV17, MPV17L, MPV17L2, MPZ, MPZL1, MPZL2, MPZL3, MR1, MRAP, MRAP2, MRAS, MRC1, MRC2, MRE11, MREG, MRFAP1, MRFAP1L1, MRGBP, MRGPRD, MRGPRE, MRGPRF, MRGPRG 、MRGPRX1、MRGPRX2、MRGPRX3、MRGPRX4、MRI1、MRLN、MRM1、MRM2、MRM3、MR NIP、MRO、MROH1、MROH2A、MROH2B、MROH5、MROH6、MROH7、MROH7-TTC4、MROH 8、MROH9、MRPL1、MRPL10、MRPL11、MRPL12、MRPL13、MRPL14、MRPL15、MRPL1 6、MRPL17、MRPL18、MRPL19、MRPL2、MRPL20、MRPL21、MRPL22、MRPL23、MRPL 24、MRPL27、MRPL28、MRPL3、MRPL30、MRPL32、MRPL33、MRPL34、MRPL35、MRP L36、MRPL37、MRPL38、MRPL39、MRPL4、MRPL40、MRPL41、MRPL42、MRPL43、MR PL44、MRPL45、MRPL46、MRPL47、MRPL48、MRPL49、MRPL50、MRPL51、MRPL52、 MRPL53、MRPL54、MRPL55、MRPL57、MRPL58、MRPL9、MRPS10、MRPS11、MRPS12 MRP S27、MRPS28、MRPS30、MRPS31、MRPS33、MRPS34、MRPS35、MRPS36、MRPS5、MRPS6、MRPS7、MRPS9、MRRF、MRS2、MRTO4、MRVI1、MS4A1 、MS4A10、MS4A12、MS4A13、MS4A14、MS4A15、MS4A2、MS4A3、MS4A4A、MS4A4E、MS4A5、MS 4A6A、MS4A6E、MS4A7、MS4A8、MSANTD1、MSANTD2、MSANTD3、MSANTD3-TMEFF1、MSANTD4 MSC, MSGN1, MSH2, MSH3, MSH4, MSH5, MSH5-SAPCD1, MSH6, MSI1, MSI2, MSL1, MSL2 MSL3, MSLN, MSLNL, MSMB, MSMO1, MSMP, MSN, MSR1, MSRA, MSRB1, MSRB2, MSRB3, MSS51, MST1, MST1R, MS TN, MSTO1, MSX1, MSX2, MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1HL1, MT1M, MT1X, MT2A, MT3, MT4, MTA1 TA2, MTA3, MTAP, MT-ATP6, MT-ATP8, MTBP, MTCH1, MTCH2, MTCL1, MT-CO1, MT-CO2, MT-CO3, MTCP1, MT-CY B、MTDH、MTERF1、MTERF2、MTERF3、MTERF4、MTF1、MTF2、MTFMT、MTFP1、MTFR1、MTFR1L、MTFR2、MTG1、MTG2 、MTHFD1、MTHFD1L、MTHFD2、MTHFD2L、MTHFR、MTHFS、MTHFSD、MTIF2、MTIF3、MTM1、MTMR1、MTMR10、MTMR11、MTMR12、MTMR14、MTMR2、MTMR3、MTMR4、MTMR6、MTMR7、MTMR8、MTMR9、MT-ND1、MT-ND2、MT-ND3、MT-ND4、MT-ND4L、MT-ND5、MT-ND6、MTNR1A、MTNR1B、MTO1、MTOR、MTPAP、MTPN、MTR、MTRF1、MTRF1L、MTRNR2L1、MTRNR2L10、MTRNR2L11、MTRNR2L12、MTRNR2L13、MTRNR2L3、MTRNR2L4、MTRNR2L5、MTRNR2L6、MTRNR2L7、MTRNR2L8、MTRR、MTSS1、MTSS1L、MTTP、MTURN、MTUS1、MTUS2、MTX1、MTX2、MTX3、MUC1、MUC12、MUC13、MUC15、MUC16、MUC17、MUC2、MUC20、MUC21、MUC22、MUC3A、MUC4、MUC5AC、MUC5B、MUC6、MUC7、MUCL1、MUL1、MUM1、MUM1L1、MUS81、MUSK、MUSTN1、MUT、MUTYH、MVB12A、MVB12B、MVD、MVK、MVP、MX1、MX2、MXD1、MXD3、MXD4、MXI1、MXRA5、MXRA7、MXRA8、MYADM、MYADML2、MYB、MYBBP1A、MYBL1、MYBL2、MYBPC1、MYBPC2、MYBPC3、MYBPH、MYBPHL 、MYC、MYCBP、MYCBP2、MYCBPAP、MYCL、MYCN、MYCT1、MYD88、MYDGF、MYEF2、MYEOV、MYF5、MYF6、MYH1、MYH10、MYH11、MYH13、MYH14、MYH15、MYH2、MYH3、MYH4、MYH6、MYH7 MYH7B、MYH8、MYH9、MYL1、MYL10、MYL12A、MYL12B、MYL2、MYL3、MYL4、MYL5、MYL6B、MYL6 7、MYL9、MYLIP、MYLK、MYLK2、MYLK3、MYLK4、MYLPF、MYMK、MYMX、MYNN、MYO10、MYO15A、MYO15B MYO16、MYO18A、MYO18B、MYO19、MYO1A、MYO1B、MYO1C、MYO1D、MYO1E、MYO1F、MYO1G、MYO1H、MYO 3A、MYO3B、MYO5A、MYO5B、MYO5C、MYO6、MYO7A、MYO7B、MYO9A、MYO9B、MYOC、MYOCD、MYOCOS、MYO D1、MYOF、MYOG、MYOM1、MYOM2、MYOM3、MYOT、MYOZ1、MYOZ2、MYOZ3、MYPN、MYPOP、MYRF、MYRFL、M YRIP. BP2L2、N4BP3、N6AMT1、A10、A11、A15、A16、A20、A25、A30、A35、A38、A4 0、NAA50、NAA60、NAA、NAME2、NAMEDL1、NASD2、NAB1、NAB2、NABP1、NABP2、NACA、NACA2 、NACAD、NACC1、NACC2、NADK、NADK2、NADSYN1、NAE1、NAF1、NAGA、NAGK、NAGLU、NAGP A、NAGS、NAIF1、NAIP、NALCN、NAMPT、NANOG、NANOGNB、NANOGP8、NANOS1、NAN OS2、NANOS3、NANP、NANS、NAP1L1、NAP1L2、NAP1L3、NAP1L4、NAP1L5、NAPA、NA PB、NAPEPLD、NAPG、NAPRT、NAPSA、NARF、NARFL、NARS、NARS2、NASP、NAT1、NA T10、NAT14、NAT16、NAT2、NAT6、NAT8、NAT8B、NAT8L、NAT9、NATD1、NAV1、NAV2 、NAV3、NAXD、NAXE、NBAS、NBDY、NBEA、NBEAL1、NBEAL2、NBL1、NBN、NBPF1、NB PF10、NBPF11、NBPF12、NBPF14、NBPF15、NBPF19、NBPF20、NBPF26、NBPF3、NBP F4、NBPF6、NBPF9、NBR1、NCALD、NCAM1、NCAM2、NCAN、NCAPD2、NCAPD3、NCAPG 、NCAPG2、NCAPH、NCAPH2、NCBP1、NCBP2、NCBP2-AS2、NCBP2L、NCBP3、NCCRP1、 NCDN、NCEH1、NCF1、NCF2、NCF4、NCK1、NCK2、NCKAP1、NCKAP1L、NCKAP5、NCKA P5L、NCKIPSD、NCL、NCLN、NCMAP、NCOA1、NCOA2、NCOA3、NCOA4、NCOA5、NCOA6、 NCOA7、NCOR1、NCOR2、NCR1、NCR2、NCR3、NCR3LG1、NCS1、NCSTN、NDC1、NDC80 、NDE1、NDEL1、NDFIP1、NDFIP2、NDN、NDNF、NDOR1、NDP、NDRG1、NDRG2、NDRG3、 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E、NFKBIL1、NFKBIZ、NFRKB、NFS1、NFU1、NFX1、NFXL1、NFYA、NFYB、NFYC、NGB、NGDN、NG EF, NGF, NGFR, NGLY1, NGRN, NHEJ1, NHLH1, NHLH2, NHLRC1, NHLRC2, NHLRC3, NHLRC4, NHP2, NHS, NHSL1, NHSL2, NICN1, NID1, NID2, NIF3L1, NIFK, NIM1K, NIN, NINJ1, NINJ2, N INL、NIP7、NIPA1、NIPA2、NIPAL1、NIPAL2、NIPAL3、NIPAL4、NIPBL、NIPSNAP1、NIPSNA P2、NIPSNAP3A、NIPSNAP3B、NISCH、NIT1、NIT2、NKAIN1、NKAIN2、NKAIN3、NKAIN4、NKAP 、NKAPL、NKD1、NKD2、NKG7、NKIRAS1、NKIRAS2、NKPD1、NKRF、NKTR、NKX1-1、NKX1-2、NK NKX2-1 6-2、NKX6-3、NLE1、NLGN1、NLGN2、NLGN3、NLGN4X、NLGN4Y、NLK、NLN、NLRC3、NLRC4、NLRC5、NLRP1、NLRP10、NLRP11、NLRP12、NLRP13、NLRP14、NLRP2、NLRP2B、NLRP3、NLRP4、NLRP5、NLRP6、N LRP7、NLRP8、NLRP9、NLRX1、NMB、NMBR、NMD3、NME1、NME1-NME2、NME2、NME3、NME4、NME5、NME6、NME7、NME8、NME9、NMI、NMNAT1、NMNAT2、NMNAT3、NMRAL1、NMRK1、NMRK2、NMS、NMT1、NMT2、NMU 、NMUR1、NMUR2、NNAT、NNMT、NNT、NOA1、NOB1、NOBOX、NOC2L、NOC3L、NOC4L、NOCT、NOD1、NOD2、NODAL、NOG、NOL10、NOL11、NOL12、NOL3、NOL4、NOL4L、NOL6、NOL7、NOL8、NOL9、NOLC1、NOM1、NO MO1、NOMO2、NOMO3、NONO、NOP10、NOP14、NOP16、NOP2、NOP53、NOP56、NOP58、NOP9、NOS1、NOS1AP、NOS2、NOS3、NOSIP、NOSTRIN、NOTCH1、NOTCH2、NOTCH2NL、NOTCH3、NOTCH4、NOTO、NOTUM、NOV ,NOVA1, NOVA2, NOX1, NOX3, NOX4, NOX5, NOXA1, NOXO1, NOXRED1, NPAP1, NPAS1, NPAS2, NPAS3, NPAS4, NPAT, NPB, NPBWR1, NPBWR2, NPC1, NPC1L1, NPC2, NPDC1, NPEPL1, NPEPPS, NPFF, NPFFR1, NPFFR2, NPHP1, NPHP3, NPHP3-ACAD11, NPHP4, NPHS1, NPHS2, NPIPA1, NPIPA2, NPIPA3, NPIPA5, NPIPA7, NPIPA8, NPIPB11, NPIPB12, NPIPB13, NPI PB15, NPIPB2, NPIPB3, NPIPB4, NPIPB5, NPIPB6, NPIPB7, NPIPB8, NPIPB9, NPL, NPLOC4, NPM1, NPM2, NPM3, NPNT, NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, NPRL2, NPRL3, NPS, NPSR1, NPTN, NPTX1, NPTX2, NPTXR, NPVF, NPW, NPY, NPY1R, NPY2R, NPY4R, NPY4R2, NPY5R, NQO1, NQO2, NR0B1, NR0B2, NR1D1, NR1D2, NR1H2, NR1H3, NR1H4, NR1I2, NR1I3, NR2C1, NR2C2, NR2C2AP, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRAP, NRARP, NRAS, NRBF2, NRBP1, NRBP2, NRCAM NRDC, NRDE2, NREP, NRF1, NRG1, NRG2, NRG3, NRG4, NRGN, NRIP1, NRIP2, NRIP3, NRK, NRL, NRM, NRN1, NRN1L, NRP1, NRP2, NRROS, NRSN1, NRSN2, NRTN, NRXN1, NRXN2, NRXN3, NSA2, NSD1, NSD2, NSD3, NSDHL, NSF, NS FL1C、NSL1、NSMAF、NSMCE1、NSMCE2、NSMCE3、NSMCE4A、NSMF、NSRP1、NSUN2、NSUN3、NSUN4、NSUN5、NSUN6 、NSUN7、NT5C、NT5C1A、NT5C1B、NT5C1B-RDH14、NT5C2、NT5C3A、NT5C3B、NT5DC1、NT5DC2、NT5DC3、NT5DC4 、NT5E、NT5M、NTAN1、NTF3、NTF4、NTHL1、NTM、NTMT1、NTN1、NTN3、NTN4、NTN5、NTNG1、NTNG2、NTPCR、NTRK 1、NTRK2、NTRK3、NTS、NTSR1、NTSR2、NUAK1、NUAK2、NUB1、NUBP1、NUBP2、NUBPL、NUCB1、NUCB2、NUCKS1、NU DC、NUDCD1、NUDCD2、NUDCD3、NUDT1、NUDT10、NUDT11、NUDT12、NUDT13、NUDT14、NUDT15、NUDT16、NUDT16L 1、NUDT17、NUDT18、NUDT19、NUDT2、NUDT21、NUDT22、NUDT3、NUDT4、NUDT4P1、NUDT5、NUDT6、NUDT7、NUDT8 NUDT9、NUF2、NUFIP1、NUFIP2、NUGGC、NUMA1、NUMBER、NUMBLE、NUP107、NUP133、NUP153、NUP155 NUP160、NUP188、NUP205、NUP210、NUP210L、NUP214、NUP35、NUP37、NUP43、NUP50、NUP54、NUP 58、NUP62、NUP62CL、NUP85、NUP88、NUP93、NUP98、NUPL2、NUPR1、NUPR2、NUS1、NUSAP1、NUTF2、 NUTM1、NUTM2A、NUTM2B、NUTM2D、NUTM2E、NUTM2F、NUTM2G、NVL、NWD1、NWD2、NXF1、NXF2、NXF2B 、NXF3、NXF5、NXN、NXNL1、NXNL2、NXPE1、NXPE2、NXPE3、NXPE4、NXPH1、NXPH2、NXPH3、NXPH4 T1、NXT2、NYAP1、NYAP2、NYNRIN、NYX、OAF、OARD1、OAS1、OAS2、OAS3、OASL、OAT、OAZ1、OAZ2、OA Z3、OBP2A、OBP2B、OBSCN、OBSCN-AS1、OBSL1、OC90、OCA2、OCEL1、EYEK1、EYE2、OCLM、OCLN、 OCM、OCM2、OCRL、OCSTAMP、ODAM、ODC1、ODF1、ODF2、ODF2L、ODF3、ODF3B、ODF3L1、ODF3L2、ODF4 、OFCC1、OFD1、OGDH、OGDHL、OGFOD1、OGFOD2、OGFOD3、OGFR、OGFRL1、OGG1、OGN、OGT、OIP5、OIT3、OLA1、OLAH、OLFM1、OLFM2、OLFM3、OLFM4、OLFM1、OLFM1 L2A、OLFML2B、OLFML3、OLIG1、OLIG2、OLIG3、OLR1、OMA1、OMD、OMG、OMP、ONECUT1、ONECUT2、ONECUT3、OOEP、OOSP2、OPA1、OPA3、OPALIN、OPCML、OPHN1、OP LAH、OPN1LW、OPN1MW、OPN1MW2、OPN1MW3、OPN1SW、OPN3、OPN4、OPN5、OPRD1、OPRK1、OPRL1、OPRM1、OPRPN、OPTC、OPTN、OR10A2、OR10A3、OR10A4、OR10A5 OR10A6、OR10A7、OR10AC1、OR10AD1、OR10AG1、OR10C1、OR10D3、OR10G2、OR10G3、OR10G4、OR10G6、OR10G7、OR10G8、OR10G9、OR10H1、OR10H2、OR10H3、OR10G1 0H4、OR10H5、OR10J1、OR10J3、OR10J4、OR10J5、OR10K1、OR10K2、OR10P1、OR10Q1、OR10R2、OR10S1、OR10T2、OR10V1、OR10W1、OR10X1、OR10Z1、OR11A1、O R11G2、OR11H1、OR11H12、OR11H2、OR11H4、OR11H6、OR11H7、OR11L1、OR12D1、OR12D2、OR12D3、OR13A1、OR13C2、OR13C3、OR13C4、OR13C5、OR13C7、OR13C8 、OR13C9、OR13D1、OR13F1、OR13G1、OR13H1、OR13J1、OR14A16、OR14A2、OR14C36、OR14I1、OR14J1、OR14K1、OR1A1、OR1A2、OR1B1、OR1C1、OR1D2、OR1D5、OR15 R1E1、OR1E2、OR1F1、OR1G1、OR1I1、OR1J1、OR1J2、OR1J4、OR1K1、OR1L1、OR1L3、OR1L4、OR1L6、OR1L8、OR1M1、OR1N1、OR1N2、OR1P1、OR1Q1、OR1S1、OR1S2OR2A1, OR2A12, OR2A14, OR2A2, OR2A25, OR2A4, OR2A42, OR2A5, OR2A7, OR2AE1, OR2AG1, OR2AG2, OR2AJ1, OR2AK2, OR2AP1, OR2AT4, OR2B11, OR2B2, OR2B3, OR2B6 OR2C1, OR2C3, OR2D2, OR2D3, OR2F1, OR2F2, OR2G2, OR2G3, OR2G6, OR2H1, OR2H2, OR2J1, OR2J2, OR2J3, OR2K2, OR2L13, OR2L2, OR2L3, OR2L5, OR2L8, OR2M2, OR2M 3、OR2M4、OR2M5、OR2M7、OR2S2、OR2T1、OR2T10、OR2T11、OR2T12、OR2T2、OR2T27、 OR2T29、OR2T3、OR2T33、OR2T34、OR2T35、OR2T4、OR2T5、OR2T6、OR2T7、OR2T8、OR 2V1, OR2V2, OR2W1, OR2W3, OR2Y1, OR2Z1, OR3A1, OR3A2, OR3A3, OR4A15, OR4A16, OR4A47, OR4A5, OR4A8, OR4B1, OR4C11, OR4C12, OR4C13, OR4C15, OR4C16, OR4C3 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Claims

1. Formula I: 【Chemistry 1-1】 or a pharmaceutically acceptable salt thereof, wherein: X １ is the divalent moiety —C(O)—; R １ represents hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ２ R, -NR ２ or optionally substituted C １～４ is aliphatic; Each R ２ are independently hydrogen, R ６ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , or -N(R)S(O) ２ R; Ring A is [Chemistry 1-3] and Ring B 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; Each R ４ are independently hydrogen, R ６ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , or -N(R)S(O) ２ R; Each R ６ is independent, C １～６ 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 is a covalent bond or a divalent, saturated or unsaturated, straight or branched chain C １～５０ a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -NRS(O) ２ -, -S(O) ２ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [Chemistry 1-4] has been replaced by, where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-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 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBM is a target binding moiety, wherein said target binding moiety is: [Chemistry 1-5] an ABL-binding moiety selected from: m is 0, 1, 2, 3 or 4; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 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 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, 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 or a pharmaceutically acceptable salt thereof.

2. X １ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is —C(O)—.

3. R １ represents hydrogen, halogen, -OR, -SR, -S(O)R, -S(O) ２ R, -NR ２ or optionally substituted C １～４ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is aliphatic.

4. Ring A is 【Chemistry 4】 2. The compound of claim 1, wherein:

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a 6-membered aryl containing 0 to 2 nitrogen atoms, a 6-membered partially saturated carbocyclyl, or a 6-membered partially saturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. R ４ is hydrogen, R ６ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , or -N(R)S(O) ２ R or a pharmaceutically acceptable salt thereof.

7. L is a divalent, saturated or unsaturated, straight or branched chain C １～２０ a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -NRS(O) ２ -, -S(O) ２ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 【Transformation 7】 2. The compound of claim 1, wherein R is 0 or R is 1; or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the TBM targets ABL1, ABL2, or an ABL gene fusion product.

9. The compound is: 【Chemistry 10】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

11. A method for degrading a target protein in a biological sample, comprising contacting the sample with a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. A method that encompasses a process.

12. 11. The pharmaceutical composition of claim 10 for the treatment of a disorder, disease, or condition mediated by a target protein in a patient, comprising administering the compound or composition to the patient.

13. 13. The pharmaceutical composition of claim 12, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder.

14. 14. The pharmaceutical composition of claim 13, wherein the disorder is a proliferative disorder.

15. 15. The pharmaceutical composition of claim 14, wherein the proliferative disorder is cancer.

16. These cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; multiple myeloma; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, 16. The pharmaceutical composition of claim 15, wherein the cancer is a sarcoma, including fistula, ganglioneuroma, ganglioglioma, medulloblastoma, pineal tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, or Philadelphia chromosome positive CML.

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