TYK2 DEGRADERS AND THEIR USES

Abstract

The present invention provides compounds, compositions thereof, and methods of using them.For example, compounds and compositions thereof are useful for targeting, inhibiting, and / or degrading TYK2.In certain embodiments, TYK2 inhibitors and / or degraders are provided, as well as methods of making them.More specifically, TYK2 degraders, compositions containing TYK2 degraders, and methods of treating conditions related to TYK2 are provided.

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 271,648 (filed October 25, 2021), the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of tyrosine kinase 2 (TYK2) protein by ubiquitination and / or degradation by compounds according to the invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using said compositions in the treatment of various disorders. [Background technology]

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

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

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

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

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents and provide a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46).

[0008] TYK2 is an enzyme encoded by the TYK2 gene in humans and is a member of the Janus kinase (JAK) family of proteins. TYK2 is involved in IL-12, IL-23, and type I interferon (IFN) signaling (Morris R, et al., Protein Science, Volume: 27, Issue: 12, Pages: 1984-2009, 2018). Studies of human genes suggest that inhibition of TYK2 may be broadly beneficial for treating autoimmune and inflammatory diseases (Dendrou C, et al., Science Translational Medicine, Vol. 8, Issue 363, p. 363ra149 2016). There is a continuing need in the art for effective treatments of disorders, particularly autoimmune and inflammatory diseases, and disorders mediated by inflammatory molecules such as IFN-α / β, IL-12, and IL-23, without JAK 1 / 2 inhibition, which can cause on-target adverse events. Thus, small molecule therapeutics that affect E3 ligase-mediated proteolysis to pro-inflammatory associated proteins, such as tyrosine kinase 2 (TYK2), while potentially not recruiting molecules such as IL-10 and IL-22, which are involved in wound healing and protection against microorganisms, hold promise as therapeutic agents for the treatment of conditions such as Crohn's disease and ulcerative colitis. Thus, there remains a need to find compounds that are TYK2 degraders, useful as therapeutic agents. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Li et al. (PLOS One, 2008, 3, 1487) Title: "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling." [Non-patent document 2] Berndsen et al. (Nat.Struct.Mol.Biol.,2014,21,301-307) Title: “New insights into ubiquitin E3 ligase mechanism” [Non-patent document 3] Deshaies et al. (Ann.Rev.Biochem.,2009,78,399-434) Title: "RING domain E3 ubiquitin ligases." [Non-patent document 4] Spratt et al. (Biochem.2014,458,421-437) Title: "RBR E3 ubiquitin ligases: new structures, new insights, new questions." [Non-Patent Document 5] Wang et al. (Nat.Rev.Cancer.,2014,14,233-347) Title: "Roles of F-box proteins in cancer." [Non-patent document 6] Crews C,Chemistry & Biology,2010,17(6):551-555 [Non-Patent Document 7] Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 [Non-patent document 8] Morris R,et al.,Protein Science,Volume:27,Issue:12,Pages:1984-2009,2018 [Non-Patent Document 9] Dendrou C, et al.,Science Translational Medicine,Vol 8,Issue 363,p.363ra149 2016 Summary of the Invention [Means for solving the problem]

[0010] Summary of the Invention The present application relates to novel bifunctional compounds that function to recruit TYK2 protein to E3 ubiquitin ligase 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 TYK2 protein, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. Also provided are monovalent compounds that find utility as inducers of targeted ubiquitination of TYK2 protein, which are then degraded and / or otherwise inhibited by the monovalent compounds described herein. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, consistent with the degradation / inhibition of TYK2 protein. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or alleviation of disease conditions, such as cancer.

[0011] The present application further relates to targeted degradation of TYK2 protein through the use of bifunctional molecules, including bifunctional molecules that combine a cereblon-binding moiety with a ligand that binds to TYK2 protein.

[0012] It has now been found that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of TYK2 protein. Such compounds have the general formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0013] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving the TYK2 protein, including those described herein.

[0014] The compounds provided by the present invention are also useful for studying TYK2 protein in biological and pathological phenomena; studying intracellular signaling pathways occurring in body tissues; and comparative evaluation, in vitro or in vivo, of new TYK2 inhibitors or TYK2 degraders or other regulators of cell cycle, metastasis, angiogenesis, and immune cell evasion. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of Specific Embodiments Detailed embodiments of the present invention are disclosed herein. However, it should be understood that the disclosed embodiments are merely exemplary of the present invention, which may be embodied in various forms. Furthermore, each of the examples given in connection with various embodiments of the present invention is intended to be illustrative, not restrictive. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art to variously utilize the present invention.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0017] General Description of Specific Embodiments The compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of one or more TYK2 proteins.

[0018] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (I): TBM is a TYK-binding moiety capable of binding to TYK2 protein; L is a bivalent moiety connecting TBM to DIM; and DIM is a degradation-inducing moiety selected from a ligase binding moiety (LBM) and a lysine mimetic, or a hydrogen atom.

[0019] Compounds and Definitions: The compounds of the present invention include those generally described above and are further exemplified 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, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0020] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring can be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring can contain one or more oxo (=O) or thioxo (=S) substituents. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0021] 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 6 to 12 (e.g., 6 to 12) ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Without limitation, a bridged bicyclic group can contain two or more bridges (e.g., adamantanyl). Exemplary bridged bicyclic groups include: [ka] [ka] These include, but are not limited to:

[0022] 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.

[0023] 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.

[0024] 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)).

[0025] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] The term "cyclopropyl" refers to a divalent cyclopropyl group.

[0030] The term "halogen" means F, Cl, Br, or I.

[0031] 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.

[0032] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0033] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 3- 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).

[0034] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). In some embodiments, the heterocyclic ring may be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. The heterocyclyl ring may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0035] 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.

[0036] As described herein, compounds of the present disclosure may contain "substituted" moieties. In general, the term "substituted" 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 allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0037] 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 ○ -NO2; -CN; -N3; ​​-(CH2) 0~4N(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) 0~4SSR ○ ;-(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- (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, and 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, and sulfur, which can be substituted as defined below.

[0038] 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, and sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0039] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O, =S, =NNR', =NNHC(O)R', =NNHC(O)OR', =NNHS(O)R', =NR', =NOR', -O(C(R')) 2~3 O-, or -S(C(R'2)) 2~3 S-, where each independent occurrence of R' is hydrogen, C which may be substituted as defined below. 1~6 An "optionally substituted" group is an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of the "optionally substituted" group include -O(CR'2) 2~3 and R' is H, C, which may be substituted as defined below. 1~6 It is selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] Suitable substituents on the aliphatic group of R' 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, and sulfur.

[0041] 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, and 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, and sulfur.

[0042] 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, and sulfur.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0044] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. In some embodiments, provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using acidic or basic mobile phases during chromatography. Salt forms of provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and will be readily apparent to those skilled in the art.

[0045] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0046] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0047] The term "prodrug" refers to a compound that is made more active in vivo. The compound may also exist as a prodrug, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes chemical changes under physiological conditions to provide the compound. Thus, a prodrug can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, for example, in some situations, they may be easier to administer than the compound, i.e., the parent drug. For example, a prodrug may be orally bioavailable, while the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, for example, those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One example, without limitation, of a prodrug is a compound that is administered as an ester (the "prodrug") but is metabolically hydrolyzed to the active entity, a carboxylic acid. Further examples include peptidyl derivatives of a compound. The term "therapeutically acceptable prodrug" refers to a prodrug or zwitterion that is suitable for use in contact with a patient's tissues without undue toxicity, irritation, and allergic response, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0048] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits TYK2 kinase 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.

[0049] As used herein, the term "degrading agent" is defined as a heterobifunctional compound that binds and / or inhibits both TYK2 kinase and E3 ligase with measurable affinity, resulting in ubiquitination and subsequent degradation of TYK2 kinase. In certain embodiments, a degrading agent has a DC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 As used herein, the term "monovalent" refers to a degrader compound that does not have an E3 ligase binding moiety attached.

[0050] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41; 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17; 52-57.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0055] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in TYK2 kinase activity between a sample containing a compound of the present invention or a composition thereof and TYK2 kinase and an equivalent sample containing TYK2 kinase in the absence of the compound or composition thereof.

[0056] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and / or steps of the type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0057] The term "treat" or "treatment" of a condition, disease, or condition includes: (1) preventing, delaying, or reducing the incidence and / or likelihood of appearance of at least one clinical or subclinical symptom of the condition, disease, or condition that has developed in a subject who may be afflicted with or susceptible to the condition, disease, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disease, or condition; or (2) inhibiting the condition, disease, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence and at least one clinical or subclinical symptom thereof; or (3) alleviating the disease, i.e., causing regression of the condition, disease, or condition, or at least one of its clinical or subclinical symptoms. The benefit to the subject to be treated is either statistically significant or at least perceptible to the patient or physician. 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 before 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.

[0058] "Subject" or "patient" or "individual" or "animal," as used herein, refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of disease (e.g., mice, rats). In a preferred embodiment, the subject is a human.

[0059] As used herein, the term "effective" as applied to dose or amount refers to the amount of a compound or pharmaceutical composition that is sufficient to produce the desired activity when administered to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include the amount of each ingredient that is effective when administered individually. The exact amount required will vary from subject to subject, depending on the species, age and general health of the subject, the severity of the condition being treated, the specific drug(s) used, and the mode of administration, etc.

[0060] The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medical response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

[0061] Ranges may be expressed herein as from "about" or "approximately" one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0062] "Comprising" or "containing" or "including" means that at least the named compounds, elements, particles, or method steps are present in the composition or article or method, but does not exclude the presence of other compounds, elements, particles, or method steps, even if such other compounds, elements, particles, or method steps have the same function as the named ones.

[0063] 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 phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0064] "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, a compound of this invention or an inhibitory or degradative active metabolite or residue thereof.

[0065] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of the TYK2 protein or a variant thereof.

[0066] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of the TYK2 protein or a variant thereof.

[0067] TYK2 binding part (TBM) In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (I), TBM is a TYK binding moiety capable of binding to a TYK2 protein; L is a bivalent moiety connecting TBM to DIM; and DIM is a degradation-inducing moiety selected from a ligase binding moiety (LBM) and a lysine mimetic, or a hydrogen atom.

[0068] In some embodiments, the TBM is a TYK2 protein binding moiety. Such TYK2 binders are well known to those skilled in the art and are described in WO 2010 / 000089A1; WO 2012 / 000970A1; WO 2012 / 062704A1; WO / 2012 / 066061A1; WO 2013 / 174895A1; WO 2014 / 074660; WO 2014 / 074661; WO 2014 / 074670; WO 2015 / 032423; WO 2015 / 069310; WO 2015 / 089143; WO 2015 / 091584A1; WO 2015 / 131080A1; WO 2016 / 138352A1; US 2017 / 0240552;WO 2017 / 040757A1;WO 2017 / 087590;WO 2018 / 067432;WO 2018 / 071794A1;WO 2018 / 075937A1;WO 2019 / 081488;WO 2018 / 093968;WO 2018 / 111787;WO 2018 / 165240A1;WO 2019 / 023468A1;WO 2019 / 183186;US 2020 / 0231594;WO 2020 / 074461A1;WO 2020 / 081508A1;WO 2020 / 086616A1;WO 2020 / 092196;WO 2020 / 112937A1;WO 2020 / 154474A1;WO 2020 / 159904;WO 2020 / 163778A1;WO 2020 / 185755A1;WO 2020 / 198379A1;WO 2020 / 222773A1;WO 2020 / 223431A1;WO 2021 / 048618A1;WO 2021 / 048620A1;WO 2021 / 092246A1;WO 2021 / 055651A1 2021 / 055652A1;WO 2021 / 180072A1;WO 2022 / 166917;CN114805438;WO 2022 / 165141;WO 2022 / 156657;WO 2022 / 150446;WO 2022 / 135430;WO 2022 / 127869;WO 2022 / 121868;WO 2022 / 117090;WO 2022 / 105771;WO 2022 / 109492;WO 2022 / 099431;WO 2022 / 060973;CN114181199;WO 2022 / 032484;CN114057651;CN 113773262;WO 2021 / 259208;US 2022 / 002267;US 2022 / 0009910;WO 2022 / 011337;WO 2022 / 011338;WO 2022 / 017494;CN113968846;CN 113698403;CN 113563309;WO 2020 / 207476;WO 2020 / 154474;WO 2020 / 185755;CN112592345;WO 2021 / 198379;WO 2021 / 170046;WO 2021 / 204626;WO 2021 / 092246;CN111909140;WO 2021 / 027647;CN 113735836;CN113735837;CN 113735859;WO 2021 / 202652;CN110818641;WO 2021 / 237121;WO 2021 / 222153;CN113666877;CN113480543;CN112142675;WO 2020 / 112937;WO 2021 / 211741;CN112159394;CN111961037;WO 2020 / 259584;WO 2020 / 163778;WO 2020 / 081508;WO 2020 / 074461;WO 2016 / 047678;WO 2020 / 156311;WO 2020 / 038457;WO 2020 / 222773;WO 2020 / 223431;US 10;517;876;JP2016065023;WO 2021 / 078020;WO 2021 / 078023;WO 2021 / 078022;WO 2020 / 086616;DE102009001438;DE102009015070;WO 2015 / 091584;US 10;308;646;WO 2019 / 023468;WO 2019 / 023468;WO 2013 / 174895;US 2021 / 087154;WO 2013 / 125543;WO 2018 / 071794;WO 2013 / 146963;WO 2015 / 016206;WO 2018 / 075937;WO 2017 / 040757;WO 2012 / 000970;WO 2016 / 027195;WO 2016 / 138352;WO 2015 / 131080;Examples include those described in WO 2011 / 113802; WO 2012 / 062704; WO 2007 / 070514; WO 2022 / 213980; WO 2022 / 206705; WO 2022 / 193499; WO 2022 / 188796; WO 2022 / 175745; WO 2022 / 175746; WO 2022 / 175747; WO 2022 / 175752; and CN114907326, each of which is incorporated herein by reference in its entirety.

[0069] In some embodiments, the compound of the present invention has the formula (IIAA'): [ka] or a pharmaceutically acceptable salt thereof, wherein when Q is attached to only a single bond, Q is independently selected in each occurrence from -CH- and -N-, or when Q is attached to a double bond, Q is -C=; R 1 is selected from hydrogen, C1-C6 aliphatic, Ring 1, -C1-C6 alkylene-Ring 1, and -Ring 1'-C1-C6 aliphatic; wherein each of said C1-C6 aliphatic, said Ring 1, said C1-C6 alkylene-Ring 1, and said -Ring 1'-C1-C6 aliphatic is independently selected from -F, -Cl, -Br, -I, and -OR C substituted as necessary with one or more of: R 2A is a covalent bond, C1~C 12 alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; 12 alkylene, and Ring 2A; or R 2A is -C1~C 12 alkylene-Ring 2A-, -Ring 2A-Z-, or -(Ring 2A)-Z-(Ring 2A)-, where R 2A is -(ring 2A)-Z5-(ring 2A)-, the two rings 2A may be the same or different; 12The alkylene and each of the rings 2A independently represent one or more R K with substitution as necessary; R 3 is selected from hydrogen and C1-C6 aliphatic, which optionally contains 1 to 8 heteroatoms independently selected from O, N, and S, and wherein the C1-C6 aliphatic is selected from one or more R K with substitution as necessary; Z1 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z2 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z3 is a covalent bond, -O-, or -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(RC )C(O)O-; Z4 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z5 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 2A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Each R K are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-( C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-N H2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic) -CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), -SCN, -NCS, -NSO, -SS(C1~C6 aliphatic), -SO2(C1~C6 aliphatic), -SO2 -N(C1~C6 aliphatic)2, -S(O)-O(C1~C6 aliphatic), -S(O)-C1~C6 aliphatic, -Si(C1~C6 aliphatic)3, -CF3, -O-CF3, two R's that are C1~C6 aliphatic or bonded to the same carbon or sulfur atom K The groups, if necessary, join together to form =O; Each R C are independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; and [ka] represents the point of attachment to L.

[0070] In some embodiments, the compound of the present invention has the formula (IIA-L-DIM) or the formula (IIB-L-DIM): [ka] or a pharmaceutically acceptable salt thereof, wherein Q, Z1, Z2, Z3, Z4, R1 , R 2A , R 2B , R 3 , L, and DIM are as defined below.

[0071] In some embodiments, the TBM has formula (IIA'), formula (IIA"), or formula (IIB): [ka] or a pharmaceutically acceptable salt thereof, wherein when Q is attached to only a single bond, Q is independently selected in each occurrence from -CH- and -N-, or when Q is attached to a double bond, Q is -C=; R 1 is selected from hydrogen, C1-C6 aliphatic, Ring 1, -C1-C6 alkylene-Ring 1, and -Ring 1'-C1-C6 aliphatic; wherein each of the C1-C6 aliphatic, the C1-C6 alkylene, the Ring 1, the -C1-C6 alkylene-Ring 1, and the -Ring 1'-C1-C6 aliphatic is independently selected from -F, -Cl, -Br, -I, and -OR C substituted as necessary with one or more of: R 2A is a covalent bond, C1~C 12 alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; 12 alkylene, and Ring 2A; or R 2A is -C1~C 12 alkylene-Ring 2A-, -Ring 2A-Z-, or -(Ring 2A)-Z-(Ring 2A)-, where R 2A is -(ring 2A)-Z5-(ring 2A)-, the two rings 2A may be the same or different; 12 The alkylene and each of the rings 2A independently represent one or more R K with substitution as necessary; R 2Bis selected from hydrogen, C1-C6 aliphatic, and Ring 2B, or R 2B is -C1-C6 alkylene-Ring 2B, -Ring 2B'-C1-C6 aliphatic, -Ring 2B'-Z5-Ring 2B, wherein each of the C1-C6 aliphatic, the C1-C6 alkylene, the Ring 2B, and the Ring 2B' independently represents one or more R K with substitution as necessary; R 3 is selected from hydrogen and C1-C6 aliphatic, which optionally contains 1 to 8 heteroatoms independently selected from O, N, and S, and wherein the C1-C6 aliphatic is selected from one or more R K with substitution as necessary; Z1 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z2 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z3 is a covalent bond, -O-, or -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(RC )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z4 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z5 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 2A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 2B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; and Ring 2B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Each R K are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-( C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-N H2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic) -CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), -SCN, -NCS, -NSO, -SS(C1~C6 aliphatic), -SO2(C1~C6 aliphatic), -SO2 -N(C1~C6 aliphatic)2, -S(O)-O(C1~C6 aliphatic), -S(O)-C1~C6 aliphatic, -Si(C1~C6 aliphatic)3, -CF3, -O-CF3, two R's that are C1~C6 aliphatic or bonded to the same carbon or sulfur atom K The groups, if necessary, join together to form =O; Each R C are independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; and [ka] represents the point of attachment to L.

[0072] In some embodiments, the TBM has the formula (IIA-1): [ka] or a pharmaceutically acceptable salt thereof, where When Q is attached to only a single bond, Q is independently selected in each occurrence from -CH- and -N-, or when Q is attached to a double bond, Q is -C=; R 1 is one or more R * and -Cy-H, optionally substituted with combinations thereof; Ring W is a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R* , -Si(R * )3, -CF3, -O-CF3 and combinations thereof; Ring X is absent or a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R *)3, -CF3, -O-CF3 and combinations thereof; R 3 is an aliphatic C1-C optionally containing 0 to 8 heteroatoms selected from halogen, O, N, and S; 12 It is a hydrocarbon; Z1 is -C(O)N(R * )-and; Z2 is a covalent bond and -NR * -Selected from; Z4 is a covalent bond, -C(O)O-, and -C(O)N(R * )-selected from Z5 is a covalent bond, -O-, -NR * -, -S-, C(R * )2-, --C(O)-, C(O)O-, and -C(O)N(R * )-selected from Each R * are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1 ~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHN H2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic) or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * the groups, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S; and [ka] represents the point of attachment to the linker L.

[0073] In some embodiments, the TBM has formula (IIA'-1) or formula (IIA"-1): [ka] [ka] or a pharmaceutically acceptable salt thereof, Here, Q and R 1 , ring 1, ring 1', R 3 , R k , R c , and [ka] is defined above, Ring W is a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K with substitution as necessary; Ring X is absent or a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and this ring is selected from one or more R K with substitution as necessary; Z1 is -C(O)N(R C )-and; Z2 is a covalent bond and -NR C -Selected from; Z4 is a covalent bond, -C(O)O-, and -C(O)N(R C )-selected from Z5 is a covalent bond, -O-, -NR C -, -S-, C(R C )2-, -C(O)-, C(O)O-, and -C(O)N(R C )- is selected from.

[0074] In some embodiments, the TBM has formula (IIA-2) and formula (IIA-3): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the TBM has the formula (IIB-1): [ka] or a pharmaceutically acceptable salt thereof, where Q is as defined above; R 1 is -Cy-H optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -N3, -NH2, -CF3, and combinations thereof; Ring W is a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR* , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R * )3, -CF3, -O-CF3 and combinations thereof; Ring X' is absent or is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R *, -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R * )3, -CF3, -O-CF3 and combinations thereof; Z1 is -C(O)N(R * )-and; Z2 is a covalent bond and -NR * -Selected from; Z5 is a covalent bond, -O-, -NR * -, -S-, C(R * )2-, --C(O)-, C(O)O-, and -C(O)N(R * )-selected from Each R * are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1 ~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHN H2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic) or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * the groups, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S; and [ka] represents the point of attachment to L.

[0076] In some embodiments, the TBM is represented by Formula (IIA'-2) through Formula (IIA'-7) and Formula (IIA"-2) through Formula (IIA"-7): [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , Z1, Z2, Z4, Z5, Ring 1, Ring 1', R k , R c , and [ka] is defined above, Ring W is a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K with Ring X is absent or a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and this ring is selected from one or more R K has been substituted as necessary.

[0077] In some embodiments, the TBM has the formula (IIB-1): [ka] or a pharmaceutically acceptable salt thereof, Here, Q and R 1, ring 1, ring 1', R k , R c , and [ka] is defined above; Ring W is absent or a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and this ring is selected from one or more R K with substitution as necessary; Ring X' is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K with substitution as necessary; Z1 is -C(O)N(R C )-and; Z2 is a covalent bond and -NR C - selected from; and Z5 is a covalent bond, -O-, -NR C -, -S-, C(R C )2-, --C(O)-, C(O)O-, and -C(O)N(R C )-selected from;

[0078] In some embodiments, the TBM has formula (IIA-2′) and formula (IIA-3′): [ka] or a pharmaceutically acceptable salt thereof.

[0079] As defined above and described herein, ring W is selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0080] In some embodiments, ring W is a ring selected from phenylenyl, 5- to 6-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K has been substituted as necessary.

[0081] As defined above and described herein, ring X is absent or a ring selected from phenylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0082] In some embodiments, ring X is absent or is a ring selected from phenylenyl, 4- to 6-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K has been substituted as necessary.

[0083] As defined above and described herein, ring X' is a ring selected from phenyl, a 4- to 6-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which may be selected from one or more R K has been substituted as necessary.

[0084] R as defined above and described herein 2B is hydrogen, aliphatic C1-C 20 Hydrocarbons, -Cy-H, C1-C 20 Alkylene -Cy-H, -Cy-C 20 aliphatic, where R 1 If is not hydrogen, then R 1 further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and R 1 -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R* , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R * )3, -CF3, -O-CF3, where: -Cy- is phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, is an optionally substituted ring selected from partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, and combinations thereof; Each R * are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1 ~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHN H2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic) or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * The groups, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from N, O, and S.

[0085] In some embodiments, R 2B is selected from hydrogen, a C1-C6 aliphatic, and Ring 2B, wherein the C1-C6 aliphatic and the Ring 2B are selected from one or more R K has been substituted as necessary.

[0086] As defined above and described herein, Ring 2B is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S.

[0087] In some embodiments, R 2B teeth, [ka] is.

[0088] In some embodiments, R 2B teeth, [ka] is.

[0089] -Z2-R as defined above and described herein 2B teeth: [ka] [ka] wherein Q is independently in each occurrence -C-, -N-, or -O-, and R * is, independently at each occurrence, hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), - SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0090] In some embodiments, -Z2-R 2B teeth: [ka] is selected from.

[0091] R as defined above and described herein 1 is hydrogen, aliphatic C1-C 20 Hydrocarbons, -Cy-H, C1-C 20 Alkylene -Cy-H, -Cy-C 20 aliphatic, where R 1 If is not hydrogen, then R 1further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and R 1 -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R * )3, -CF3, -O-CF3, where: -Cy- is phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, is an optionally substituted ring selected from partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, and combinations thereof; Each R * are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1 ~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHN H2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic) or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * the groups, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S;

[0092] In some embodiments, R 1 is selected from hydrogen, Ring 1, -Ring 1'-C1-C6 aliphatic, where the Ring 1 or the -Ring 1'-C1-C6 aliphatic is selected from -F, -Cl, -Br, -I, and -OR C substituted as needed with one or more of:

[0093] In some embodiments, R 1is a 3- to 7-membered saturated or partially unsaturated carbocyclylenyl substituted with one or more of -F, -Cl, -Br, -I, -OH, -N3, -NH2, -CF3.

[0094] In some embodiments, R 1 is hydrogen, [ka] is selected from, where R J -F, -Cl, -Br, -I, and OR c is selected from.

[0095] In some embodiments, R J is -F, -Cl, -Br, -I, -OH, -NH2, or a C1 to C6 aliphatic.

[0096] In some embodiments, R 1 teeth, [ka] is.

[0097] In some embodiments, R 1 teeth, [ka] is.

[0098] In some embodiments, R 1 teeth, [ka] is.

[0099] -Z1-R as defined above and described herein 1 is hydrogen, [ka] wherein Q is independently in each occurrence -C-, -N-, or -O-, and R * is, independently at each occurrence, hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), - SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0100] In some embodiments, -Z1-R 1 is hydrogen, [ka] is selected from, where R *is, independently at each occurrence, hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), - SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0101] In some embodiments, -Z1-R 1 teeth, [ka] In some embodiments, -Z1-R 1 teeth, [ka] In some embodiments, -Z1-R 1 teeth, [ka] In some embodiments, -Z1-R 1 teeth, [ka] is.

[0102] R as defined above and described herein 2A is -ring 2A-Z5-, or R 2A is -(Ring 2A)-Z5-(Ring 2A)-, where R 2A is -(ring 2A)-Z-(ring 2A)-, two rings 2A may be the same or different, and each ring 2A is independently an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and wherein these rings 2A independently contain one or more R K has been substituted as necessary.

[0103] In some embodiments, R 2A is a covalent bond, C1~C 12 alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; 12 alkylene, and Ring 2A, wherein the C1-C 12 Each of the alkylene and ring 2A may be one or more R K has been substituted as necessary.

[0104] In some embodiments, R 2A is hydrogen, C1 to C 20Alkylene, -Cy-, and C1-C 20 A combination of alkylene and -Cy-, where R 2A is not hydrogen, but R 2A further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and R 2A -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -C(O)-R * , -CHO, -CO2H, -CO2R * , -C(O)-SR * , -OC(O)-H, -OC(O)-R * , -SC(O)-R * , -C(O)-NH2, -C(O)-N(R * )2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(R * )2, -N(R * )-CHO, -N(R * )-C(O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(O)-OR * , -S(O)-R * , -Si(R * )3, -CF3, -O-CF3 and combinations thereof, wherein: -Cy- is phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S. an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; and R * are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1 ~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHN H2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic) or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * groups, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S;

[0105] -Z2-R as defined above and described herein 2A -Z4- is: [ka] [ka] wherein Q is independently in each occurrence -C-, -N-, or -O-, and R* is, independently at each occurrence, hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), - SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

[0106] In some embodiments, -Z2-R 2A -Z4- is: [ka] is selected from.

[0107] In some embodiments, -Z2-R 2A -Z4- is [ka] is selected from.

[0108] In some embodiments, -Z2-R 2A -Z4- is [ka] is selected from.

[0109] In some embodiments, -Z2-R 2A -Z4- is [ka] is selected from.

[0110] R as defined above and described herein 3 is selected from hydrogen and C1-C3 aliphatic, which optionally contains 1 to 8 heteroatoms independently selected from O, N, and S, and which is selected from one or more R K has been substituted as necessary.

[0111] In some embodiments, R 3 is methyl.

[0112] As defined above and described herein, Z1 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O—.

[0113] In some embodiments, Z1 is a covalent bond, -O-, or -NR C -, -C(O)-, -CR C 2-, -OC(O)-, -C(O)O-, -N(R C )C(O)-, and -C(O)N(R C )- is selected from.

[0114] In some embodiments, Z1 is —C(O)N(R c )-.

[0115] In some embodiments, Z1 is a covalent bond or -C(O)NH-.

[0116] As defined above and described herein, Z2 is a covalent bond, -O-, -NR C -, -C(O)-, -CR C 2-, -OC(O)-, -C(O)O-, -N(R C )C(O)-, and -C(O)N(R C )- is selected from.

[0117] In some embodiments, Z2 is -NR c -It is.

[0118] In some embodiments, Z2 is -NH-.

[0119] In some embodiments, Z2 is a covalent bond.

[0120] In some embodiments, Z2 is -NH- and R 2B is ring 2B.

[0121] As defined above and described herein, Z3 is a covalent bond, -O-, -NR C -, -C(O)-, -CR C 2-, -OC(O)-, -C(O)O-, -N(R C )C(O)-, and -C(O)N(R C )- is selected from.

[0122] In some embodiments, Z3 is -NH-.

[0123] As defined above and described herein, Z4 is a covalent bond, -O-, -NR C -, -C(O)-, -CR C 2-, -OC(O)-, -C(O)O-, -N(R C )C(O)-, and -C(O)N(R C )- is selected from.

[0124] In some embodiments, Z4 is a covalent bond, -O-, -C(O)-, -NH-, or -C(O)-N(CH3)-.

[0125] As defined above and described herein, Z5 is a covalent bond, -O-, -NR C -, -C(O)-, -CR C 2-, -OC(O)-, -C(O)O-, -N(R C )C(O)-, and -C(O)N(R C )- is selected from.

[0126] In some embodiments, Z5 is selected from a covalent bond and -O-.

[0127] R as defined above and described herein C is hydrogen or a C1-C6 aliphatic.

[0128] R as defined above and described herein 3 is a C1 to C6 aliphatic hydrocarbon.

[0129] In some embodiments, R 3 is an aliphatic C1 to C4 hydrocarbon.

[0130] In some embodiments, R 3 is -CH3.

[0131] In some embodiments, -Z3- is a covalent bond and R 3 is hydrogen.

[0132] In some embodiments, -Z3- is -NR C - and R 3 is -CH3.

[0133] As defined above and described herein, each R k are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, - C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic)-C(O)-(C1~C6 aliphatic), -S CN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; or: two R on the same nitrogenk The groups, together with the atoms between them, optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from N, O, and S.

[0134] In some embodiments, R K are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NH2, -NH-(C1~C6 aliphatic), -N(C1 ~C6 aliphatic)2, -N(C1~C6 aliphatic)-OH, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -C(O)-C1~C6 aliphatic aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-C(O)-(C1~C6 aliphatic), -CF3, -O-CF3, C1~C6 aliphatic group or two R's bonded to the same carbon atom K are joined together as necessary to form =O.

[0135] In some embodiments, R K is -F, -Cl, -Br, -I, -OH, -NH2, or a C1 to C6 aliphatic group.

[0136] As defined above and described herein, Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0137] As defined above and described herein, Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0138] As defined above and described herein, Ring 2A is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two thereof.

[0139] As defined above and described herein, Ring 2B is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0140] In some embodiments, the TBM has formula (IIBB'-1) or formula (IIA'A'-1): [ka] It has the following structure.

[0141] In some embodiments, the TBM has the formula (IIA'-2-1): [ka] wherein ring X' is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R K has been substituted as necessary.

[0142] In some embodiments, the TBM has the formula (IIA'-2-a): [ka] It has the following structure.

[0143] In some embodiments, the TBM comprises: [ka] where Q is -C- or -N-; and [ka] represents the point of attachment to L.

[0144] In some embodiments, the TBM has the formula (IIA'-2-a): [ka] It has the following structure.

[0145] In some embodiments, the TBM has the formula (IIA'-2-b): [ka] It has the following structure.

[0146] In some embodiments, the TBM has formula (IIA'-2-c) or formula (IIA'-2-d): [ka] It has the following structure.

[0147] In some embodiments, the TBM has formula (IIA'-2-b') or formula (IIA'-2-c'): [ka] It has the following structure.

[0148] In some embodiments, the TBM has formula (IIIAA) or formula (IIIBB): [ka] or a pharmaceutically acceptable salt thereof, U is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from N, O, and S; V is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; R 4 is hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -CN, -C(O)-C1~C6 aliphatic, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-NH2, -C (O)-NH(C1~C6 aliphatic), -C(O)-N(C1~C6 aliphatic)2, -C(O)-(C1~C6 aliphatic), -SO2(C1~C6 aliphatic), -SO2-N(C1~C6 aliphatic)2, -S(O)-C1~C6 aliphatic, -CD3, -CF3, or -O-CF3; R 5A is selected from a covalent bond and Ring 5A, wherein Ring 5A is selected from one or more R 8 with substitution as necessary; R 6A is selected from hydrogen, Ring 6A, and -Ring 6A'-Ring 6A, where Ring 6A and Ring 6A' independently represent one or more R 8 with substitution as necessary; R 5B is selected from hydrogen, Ring 5B, and -Ring 5B'-Ring 5B, wherein said Ring 5B and said Ring 5B' independently represent one or more R 8 with substitution as necessary; R 6Bis selected from a covalent bond and Ring 6B, wherein Ring 6B is selected from one or more R 8 with substitution as necessary; Ring 5A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 6A is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6A' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6B is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Z 6 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(RC )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z 7 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z 8 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Each R 7 are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 +, -N(C1-C6 aliphatic)-OH, -O-N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)-O-(C1-C6 aliphatic), -CN, -NC, -C(O)-C1-C6 aliphatic, -CHO, -CO2H, -CO2(C1-C6 aliphatic), -C(O)-S-(C1-C6 aliphatic), -O-C(O)-H, -O-C(O)-(C1-C6 aliphatic), -S-C(O)-(C1-C6 aliphatic), -C(O)-NH2, -C(O)-NH(C1-C6 aliphatic), -C(O)-N(C1-C6 aliphatic)2, -C(O)-NHNH2, -O-C(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)-CHO, -N(C1-C6 aliphatic)-C(O)-(C1-C6 aliphatic), -SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic)3, -CD3, -CF3, or -O-CF3; Each R 8 is independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1-C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1-C6 aliphatic), -N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)3 +, -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)- S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-NH(C1~C6 aliphatic), -C(O)-N(C1~C6 aliphatic)2, -C(O)-N HNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic) -CHO, -N(C1~C6 aliphatic) -C(O)-(C1~C6 aliphatic), -SCN, -NCS, -NSO, -SS(C -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CD3, -CF3, or -O-CF3; Each R C are independently hydrogen or an optionally substituted C1-C6 aliphatic group; and [ka] represents the point of attachment to L.

[0149] As defined above and described herein, U is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0150] As defined above and described herein, V is an optionally substituted ring selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S.

[0151] In some embodiments, the TBM has formula (IIIA') or formula (IIIB'): [ka] or a pharmaceutically acceptable salt thereof, where R 1 is hydrogen, R * , aliphatic C1~C 20 Hydrocarbons, -Cy-H, -Cy-C 20 Aliphatic and C1-C 20 alkylene-Cy-H, where R 1 If is not hydrogen, then R 1 further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, where R 1 is one or more R * with substitution as necessary; R 2 is a covalent bond, C1~C 20 Alkylene, -Cy-, and -C1-C 20 alkylene-Cy-, where R 2 C1~C 20 Alkylene, -Cy-, or -C1-C 20 alkylene-Cy-, R 2 further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and R 2 is one or more R * with substitution as necessary; R 3 is hydrogen, R * , aliphatic C1~C 20 Hydrocarbons, -Cy-H, -Cy-C 20Aliphatic and C1-C 20 alkylene-Cy-H, where R 3 is non-hydrogen, R 3 further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, where R 3 is one or more R * with substitution as necessary; Z1, Z2 and Z3 each independently represent a covalent bond, -O-, or -NR * -, -S-, -C(O)-, -C(S)-, -CR * 2-, -OC(O)-, -C(O)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 * )-, and -N(R * )C(O)O-; -Cy- is phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S. an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; and Each R *are independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~ C6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) ), -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic)-C(O)-(C1~C6 aliphatic), -SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CD3, -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; or: Two R on the same nitrogen * groups, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S; and [ka] represents the point of attachment to L.

[0152] In some embodiments, R 3 The structure: [ka] It has.

[0153] In some embodiments, the TDM is R 3 The structure: [ka] The compound has a structure of formula (IIIB):

[0154] In some embodiments, the TBM has formula (IIIA) or formula (IIIB): [ka] or a pharmaceutically acceptable salt thereof, wherein Q' is selected from -CH= and -N=; R 4 is hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -CN, -C(O)-C1~C6 aliphatic, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-NH2, -C (O)-NH(C1~C6 aliphatic), -C(O)-N(C1~C6 aliphatic)2, -C(O)-(C1~C6 aliphatic), -SO2(C1~C6 aliphatic), -SO2-N(C1~C6 aliphatic)2, -S(O)-C1~C6 aliphatic, -CD3, -CF3, or -O-CF3; R 5A is selected from a covalent bond and Ring 5A, wherein Ring 5A is selected from one or more R 7 with substitution as necessary; R 6A is selected from hydrogen, Ring 6A, and -Ring 6A'-Ring 6A, where Ring 6A and Ring 6A' independently represent one or more R 7 with substitution as necessary; R 5Bis selected from hydrogen, Ring 5B, and -Ring 5B'-Ring 5B, wherein said Ring 5B and said Ring 5B' independently represent one or more R 7 with substitution as necessary; R 6B is selected from a covalent bond and Ring 6B, wherein Ring 6B is selected from one or more R 7 with substitution as necessary; Ring 5A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 6A is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6A' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6B is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Z 6 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C )C(O)O-; Z 7 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C)-, and -N(R C ) is selected from C(O)O-; Z 8 is a covalent bond, -O-, -NR C -, -S-, -C(O)-, -C(S)-, -CR C 2-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R C )S(O)2-, -S(O)2N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -OC(O)N(R C )-, and -N(R C ) is selected from C(O)O-; Each R 7 is independently hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1-C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1-C6 aliphatic), -N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)3 + , -N(C1-C6 aliphatic)-OH, -O-N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)-O-(C1-C6 aliphatic), -CN, -NC, -C(O)-C1-C6 aliphatic, -CHO, -CO2H, -CO2(C1-C6 aliphatic), -C(O)-S-(C1-C6 aliphatic), -O-C(O)-H, -O-C(O)-(C1-C6 aliphatic), -S-C(O)-(C1-C6 aliphatic), -C(O)-NH2, -C(O)-NH(C1-C6 aliphatic), -C(O)-N(C1-C6 aliphatic)2, -C(O)-NHNH2, -O-C(O)-NHNH2, -C(S)-NH2, -C(S)-N(C1-C6 aliphatic)2, -N(C1-C6 aliphatic)-CHO, -N(C1-C6 aliphatic)-C(O)-(C1-C6 aliphatic), -SCN, -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic)3, -CD3, -CF3, or -O-CF3; Each R C is independently hydrogen, or an optionally substituted C1-C6 aliphatic group, and [ka] represents the point of attachment to L.

[0155] In some embodiments, the TBM has formula (IIIA-1) or formula (IIIB-1): [ka] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the TBM has formula (IIIA-2) or formula (IIIB-2): [ka] or a pharmaceutically acceptable salt thereof.

[0157] R as defined above and described herein 4 In formula (IIIA), hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -CN, -C(O)-C1~C6 Aliphatic, -CO2H, -C(O)-NH2, -C(O)-NH(C1~C6 aliphatic), -C(O)-N(C1~C6 aliphatic)2, -C(O)-(C1~C6 aliphatic), -CD3, -CF3, or -O-CF3.

[0158] In some embodiments, R 4 is hydrogen or —C(O)—NH (C1-C6 aliphatic) in formula (IIIA).

[0159] In some embodiments, R 4 is —C(O)—NH(CH) in formula (IIIA).

[0160] In some embodiments, R 4is -C(O)-NH(CH3).

[0161] R as defined above and described herein 6A is ring 6A.

[0162] As defined above and described herein, Ring 6A is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0163] As defined above and described herein, in formula (IIIA), R 6A teeth, [ka] where each R 8 are independently hydrogen, -F, -Cl, -Br, -I, -OH, or -O-(C1-C6 aliphatic).

[0164] In some embodiments, R 6A is a compound of formula (IIIA) having the structure: [ka] It has.

[0165] R as defined above and described herein 6B is ring 6B.

[0166] As defined above and described herein, Ring 6B is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0167] In some embodiments, R 6B is a compound of formula (IIIB) having the structure: [ka] where each R 8 are independently hydrogen, -F, -Cl, -Br, -I, -OH, or -O-(C1-C6 aliphatic).

[0168] R as defined above and described herein 8 are independently hydrogen, —F, —Cl, —Br, —I, or —OH.

[0169] In some embodiments, at least one R 8 is -F.

[0170] As defined above and described herein, each R 7 are independently hydrogen, -F, -Cl, -Br, -I, -OH, or -O-(C1-C6 aliphatic).

[0171] In some embodiments, at least one R 7 is non-hydrogen.

[0172] In some embodiments, one R 7 is -O-(C1-C6 aliphatic).

[0173] In some embodiments, one R 7 is -O-CH3.

[0174] As defined above and described herein, Z 6 is -NH-.

[0175] In some embodiments, the structure of formula (IIIA-3) is: [ka] or a pharmaceutically acceptable salt thereof.

[0176] As defined above and described herein, Z 7 is a covalent bond, -NR C -, -C(O)-, -NR C C(O)-, -C(O)NR C -, and -NR C C(O)NR C - is selected from.

[0177] As defined above and described herein, Z 8 is a covalent bond, -C(R C 2)-, -NR C -, -C(O)-, and -C(O)NR C - is selected from.

[0178] In some embodiments, Z 8 is -NH-.

[0179] In some embodiments, Z 8 is selected from —C(O)NH— and —C(O)NCH3—.

[0180] R as defined above and described herein 5A is a covalent bond.

[0181] In some embodiments, R 5A is ring 5A.

[0182] In some embodiments, R 5Ais a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0183] In some embodiments, in Formula (IIIA), R 5A teeth, [ka] is.

[0184] In some embodiments, the TBM comprises: [ka] [ka] wherein [ka] represents the point of attachment to L.

[0185] In some embodiments, the TBM comprises: [ka] is.

[0186] In some embodiments, the TBM comprises: [ka] wherein [ka] represents the point of attachment to L.

[0187] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, are compounds 1.1-1.8 shown below: [ka] [ka] wherein LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0188] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, are compounds 2.1-2.7 shown below: [ka] wherein LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0189] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, are compounds 2.1A-2.7A shown below: [ka] wherein LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0190] In some embodiments, the TBM is selected from the group consisting of BMS-986165, BMS-986202, PF-06826647.

[0191] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in WO 2022 / 136914, whereby the compound has formula (Ix-1): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein variable R 1 , R 2 , R 3 , R 4 , R5 , and R A each as described and defined in WO 2022 / 136914, the entirety of each of which is incorporated herein by reference.

[0192] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in WO 2022 / 109580, whereby the compound has formula (Ix-2): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein variables A, R 1 , R 5 Each of Z, Z, and m is as described and defined in WO 2022 / 109580, the entirety of each of which is incorporated herein by reference.

[0193] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in WO 2022 / 083560, whereby the compound has formula (Ix-3): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein each of the variables R1, R2, R4, A1, A2, A3, A4, A5, A6, A7, A8, and n are as described and defined in WO 2022 / 083560, the entire contents of each of which are incorporated herein by reference.

[0194] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in CN 114075220, whereby the compound has formula (Ix-4): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein variable R 1 , R 6 , R 7 , V 1 , V 2 , V 3 , V 4 , X, Y, and Z are as described and defined in CN 114075220, the entirety of each of which is incorporated herein by reference.

[0195] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in CN 114075194, whereby the compound has formula (Ix-5): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, and Z are as described and defined in CN 114075194, the entirety of each of which is incorporated herein by reference.

[0196] In some embodiments, the present invention provides a compound wherein the TBM is a binding moiety as described in WO 2019 / 178079, whereby the compound has formula (Ix-6): [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined below and as described in embodiments herein, and wherein variable R 1 , R2 , R 3 , R 4a , R 4b , X 1 , X 2 , X 3 , X 4 , and X 5 each as described and defined in WO 2019 / 178079, the entirety of each of which is incorporated herein by reference.

[0197] Decomposition induction part (DIM) In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein TBM is a TYK binding moiety capable of binding to a TYK2 protein; L is a bivalent moiety connecting TBM to DIM; and DIM is a degradation-inducing moiety selected from a ligase binding moiety (LBM) and a lysine mimetic, or a hydrogen atom.

[0198] In some embodiments, the DIM is an LBM, as described below and herein. In some embodiments, the DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to the TYK2 protein is achieved by the action of the lysine mimetic. In some embodiments, when the compound of Formula (I) binds to the TYK2 protein, the lysine mimetic moiety causes ubiquitination, thereby marking the TYK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

[0199] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] is.

[0200] In some embodiments, the DIM is selected from the LBMs illustrated in Table A below.

[0201] In some embodiments, the present invention provides a compound of formula (I-aaaa-NH): [ka] or a pharmaceutically acceptable salt thereof, wherein each of TBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0202] In some embodiments, the present invention provides a compound of formula (I-aaaa-CH—NH): [ka] or a pharmaceutically acceptable salt thereof, wherein each of TBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0203] In some embodiments, the present invention provides a compound of formula (I-aaaa-CC-CH-NH): [ka] or a pharmaceutically acceptable salt thereof, wherein each of TBM and L, both alone and in combination, is as defined above and as described in embodiments herein. In certain embodiments, the present invention provides compounds of formula (I) where DIM is a lysine mimetic. In certain embodiments, the lysine mimetic has the formula I-bbbb-1, I-bbbb-2, or I-bbbb-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and the variable R 1 , R 4 , R 5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496, the entirety of each of which is incorporated herein by reference.

[0204] In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent attachment of ubiquitin to TYK2 protein is achieved by provided compounds in which DIM is a hydrogen atom. In some embodiments, when a compound of formula (I) binds to TYK2 protein, the hydrogen moiety undergoes ubiquitination, thereby marking the TYK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

[0205] In some embodiments, the present invention provides a compound wherein DIM is a hydrogen atom, whereby the compound has formula (I-cccc): [ka] or a pharmaceutically acceptable salt thereof, wherein each of TBM and L, both alone and in combination, is as defined above and as described in embodiments herein. Ligase binding moiety (LBM) In some embodiments, the LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to those skilled in the art and are described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017, 13, 675; WO 2017 / 176708; US 2017 / 0281784; WO 2017 / 161119; WO 2017 / 176957; WO 2017 / 176958; WO 2015 / 160845; US 2015 / 0291562; WO 2016 / 197032; WO 2016 / 105518; US 2018 / 0009779; WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, US 2019 / 0076540, WO 2017 / 197046, US 2019 / 0076542, WO 2017 / 197051, US 2019 / 0076539, WO 2017 / 197055, US 2019 / 0076541, and WO 2017 / 197056 (each of which is incorporated by reference in its entirety).

[0206] As defined herein and described below, formulas may be expressed using square brackets, e.g., [ka] When depicted as: L is attached to a modifiable carbon, oxygen, or nitrogen atom in DIM or LBM, including substitution or replacement of the defined group in DIM or LBM.

[0207] In some embodiments, the LBM is an E3 ubiquitin ligase binding moiety.

[0208] In some embodiments, the E3 ubiquitin ligase binding moiety is a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety.

[0209] In certain embodiments, the present invention provides that the LBM is an IMiD-based (immunomodulatory imide drug-based) cereblon E3 ubiquitin ligase binding moiety, thereby representing Formula Ia-1, Ia-2, Ia-3, Ia-4, Ia-5, Ia-6, Ia-7, Ia-8, Ia-9, Ia-10, or Ia-11, respectively: [ka] [ka] The compound or formula I-a'-1, I-a'-2, I-a'-3, I-a'-4, I-a'-5, I-a'-6, I-a'-7, I-a'-8, I-a'-9, I-a'-10, or I-a'-11, respectively: [ka] [ka] The compound or formula I-a''-1, I-a''-2, I-a''-3, I-a''-4, I-a''-5, I-a''-6, I-a''-7, I-a''-8, I-a''-9, or I-a''-10, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and [ka] teeth, [ka] and; Y is a bond, Y1, O, NH, NR2, C(O)O, OC(O), C(O)NR2', NR2'C(O), Y1-O, Y1-NH, Y1-NR2, Y1-C(O), Y1-C(O)O, Y1-OC(O), Y1-C(O)NR2', or Y1-NR2'C(O), where Y1 is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene; X is C(O) or C(R3)2; X1-X2 are C(R3)=N or C(R3)2-C(R3)2; each R1 is independently halogen, nitro, NH2, OH, C(O)OH, C1-C6 alkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R2 is halogen, N(R a )2, NHC(O)R a , NHC(O)ORa , OR b , C3-C8 cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R2' is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and when R2' is not H, it is halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; Each R3 is independently H or C6-C 10 C1-C3 alkyl optionally substituted with aryl or 5- to 10-membered heteroaryl; each R3' is independently C1-C3 alkyl; Each R4 is independently H or C1-C3 alkyl; or two R4, together with the carbon atoms to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R5 is H, C1-C3 alkyl, F, or Cl; Each R a are independently H or C1-C6 alkyl; R b is H or tosyl; t is 0 or 1; m is 0, 1, 2, or 3; and n is 0, 1 or 2.

[0210] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0211] In certain embodiments, the present invention provides a compound wherein the LBM is a cereblon E3 ubiquitin ligase binding moiety, whereby the compound has formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 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 as needed, 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.

[0212] -(R 2 ) m is depicted on ring B, this -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R may be on ring A, and also may be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 This R 4 group or R 5 It replaces the -R group. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 This R 3 It replaces the base.

[0213] In some embodiments, the compound of formula Ib above has formula Ib-1 or formula Ib-2: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0214] In some embodiments, the compound of formula Ib above has formula Ib-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring A, L, R 1, R 2 , X 1 , and m are each as defined above.

[0215] In some embodiments, the compound of formula Ib above has formula Ib-4: [ka] or a pharmaceutically acceptable salt thereof, wherein: Each of X1, X2, and X3 independently represents a covalent bond, -CH2-, -C(O)-, -C(S)-, -NR-, or [ka] and; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 is an aliphatic group; R 2 each, independently in each occurrence, is hydrogen, 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 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; m is an integer from 0 to 4; Each R is independently at each occurrence hydrogen, -F, -Cl, -Br, -I, -OH, -O-(C1~C6 aliphatic), -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NH-(C1~C6 aliphatic), -N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)3 + , -N(C1~C6 aliphatic)-OH, -ON(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-O-(C1~C6 aliphatic), -CN, -NC, -C(O)-C1~C 6 aliphatic, -CHO, -CO2H, -CO2(C1~C6 aliphatic), -C(O)-S-(C1~C6 aliphatic), -OC(O)-H, -OC(O)-(C1~C6 aliphatic) , -SC(O)-(C1~C6 aliphatic), -C(O)-NH2, -C(O)-N(C1~C6 aliphatic)2, -C(O)-NHNH2, -OC(O)-NHNH2, -C( S)-NH2, -C(S)-N(C1~C6 aliphatic)2, -N(C1~C6 aliphatic)-CHO, -N(C1~C6 aliphatic)-C(O)-(C1~C6 aliphatic), -SCN , -NCS, -NSO, -SS(C1-C6 aliphatic), -SO2(C1-C6 aliphatic), -SO2-N(C1-C6 aliphatic)2, -S(O)-O(C1-C6 aliphatic), -S(O)-C1-C6 aliphatic, -Si(C1-C6 aliphatic), -CF3, -O-CF3, or an optionally substituted group selected from C1-C6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and combinations thereof; or Two R groups on the same nitrogen, together with the atoms between them, may optionally form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from N, O, and S.

[0216] In some embodiments, X1 and X2 are -C(O)- and X3 is -NR-, where R is hydrogen or an optionally substituted C1-C6 aliphatic group.

[0217] In some embodiments, R 1 and R 2 is hydrogen in each occurrence.

[0218] In some embodiments, ring A is a fused phenyl ring.

[0219] In some embodiments, Formula (I) has formulas Ia-11, I-a′-11, and Ia″-11: [ka] or a pharmaceutically acceptable salt thereof, where L and TBM are as defined above, and: Y is a bond, Y1, O, NH, NR2, C(O)O, OC(O), C(O)NR2', NR2'C(O), Y1-O, Y1-NH, Y1-NR2, Y1-C(O), Y1-C(O)O, Y1-OC(O), Y1-C(O)NR2', or Y1-NR2'C(O), where Y1 is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene; X is C(O) or C(R3)2; each R1 is independently halogen, nitro, NH2, OH, C(O)OH, C1-C6 alkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R2 is halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C6-C 10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R2' is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and when R2' is not H, it is halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 each aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH, CN, nitro, OH, C(O)OH, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; Each R3 is independently H or C6-C 10 C1-C3 alkyl optionally substituted with aryl or 5- to 10-membered heteroaryl; each R3' is independently C1-C3 alkyl; Each R4 is independently H or C1-C3 alkyl; or two R4, together with the carbon atoms to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R5 is H, C1-C3 alkyl, F, or Cl; Each R a are independently H or C1-C6 alkyl; R b is H or tosyl; t is 0 or 1; m is 0, 1, 2, or 3; and n is 0, 1 or 2.

[0220] In some embodiments, the E3 ubiquitin ligase binding moiety is: [ka] is selected from the group consisting of:

[0221] In some embodiments, the E3 ubiquitin ligase binding moiety is [ka] is.

[0222] In some embodiments, the E3 ubiquitin ligase binding moiety is [ka] is.

[0223] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0229] In certain embodiments, the present invention provides a method for treating a cereblon E3 ubiquitin ligase-binding moiety, whereby the LBM is a cereblon E3 ubiquitin ligase-binding moiety, such as that represented by formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom, a nitrogen atom, or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is absent, hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 and R 3a each independently represents hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4 aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is bound to; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 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 as needed, 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.

[0230] In some embodiments, the compound of formula Ic above has formula Ic-1 or formula Ic-2: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring C, ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m, and p are each as defined above.

[0231] In some embodiments, the compound of formula Ic above has formula Ic-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring C, ring D, L, R 1 , R 2 , R 3a , X 1, n, m, and p are each as defined above.

[0232] In certain embodiments, the present invention provides a method for treating a cereblon E3 ubiquitin ligase-binding moiety, whereby the LBM is a cereblon E3 ubiquitin ligase-binding moiety, such as that represented by formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from: Each or R 2 and R 3a are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1~4aliphatic, or -CN; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1; and Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 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 as needed, 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.

[0233] In some embodiments, the compound of formula Id above has formula Id-1 or formula Id-2: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring C, ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n, and p are as defined above.

[0234] In some embodiments, the compound of formula Id above has formula Id-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring C, ring D, L, LR 1 , R 2 , R 3a , X 1 , m, n, and p are as defined above.

[0235] In certain embodiments, the present invention provides a method for treating a cereblon E3 ubiquitin ligase-binding moiety, whereby the LBM is a cereblon E3 ubiquitin ligase-binding moiety, such as that represented by formula Ie: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0236] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0237] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0238] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0239] In some embodiments, the compound of formula Ie above has formula Ie-1 or formula Ie-2: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring E, ring F, ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0240] In some embodiments, the compound of formula Ie above has formula Ie-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring E, ring F, ring G, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0241] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the LBM has the formula If: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C1~6 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, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring H is a 7- to 9-membered saturated or partially unsaturated fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, or 4.

[0242] [ka] is illustrated on ring E or ring H, [ka] It is intended, and one skilled in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0243] -(R 2 ) m When the attachment points of -(R 2 ) mIt is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0244] [ka] are illustrated on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0245] In some embodiments, the compound of formula If has formula If-1 or formula If-2: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring E, ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0246] In some embodiments, the compound of formula If has formula If-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, ring E, ring H, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0247] In certain embodiments, the present invention provides a polypeptide comprising an LBM that is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the LBM is a polypeptide of formula Ig: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R)2-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1~4 It is aliphatic; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring K is a 6- to 12-membered saturated or partially unsaturated fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond, or C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, or 4.

[0248] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0249] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0250] [ka] are illustrated on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0251] In some embodiments, the compound of formula Ig above has formula Ig-1 or formula Ig-2: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0252] In some embodiments, the compound of formula Ig above has formula Ig-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: TBM, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 , and m are each as defined above.

[0253] In certain embodiments, the present invention provides a polypeptide comprising an LBM that is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a polypeptide of formula Ih-1 or Ih-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and Each R 2 are independently hydrogen, deuterium, -R6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and R 4 , R 10 , R 11 , R 15 , W 1 , W 2 and X are as defined in WO 2019 / 099868, the entirety of each of which is incorporated herein by reference.

[0254] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0255] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring where ring E or ring G is fused to ring F.

[0256] [ka] is illustrated on ring E, ring F, or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0257] As noted above, in another aspect, the present invention provides compounds having the formula Ih-3: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring M is, [ka] Selected from; X 1 , X 6 , and X 7 each independently represents a covalent bond, —CH—, —CHCF—, —SO—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X3 and X 5 each is independently a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] is a trivalent moiety selected from: Each R is independently hydrogen or an optionally substituted group, 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, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3a are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1~6an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1~4 Is aliphatic; or R 7 and X 1 or X 3 together with the atoms therebetween to form a 5- to 7-membered, saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; Two R on the same carbon 7 groups, optionally taken together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; Two R on adjacent carbon atoms 7 groups, optionally taken together with the atoms therebetween, form a 3- to 7-membered, saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 7- to 13-membered, saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; Ring D is selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond, or C 1~3 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0258] X, as defined above and described herein; 1 , X 6 , and X 7 each independently represents a covalent bond, —CH—, —C(R)—, —C(O)—, —C(S)—, —CH(R)—, —CH(CF)—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR)—, —S(O)—, —S(O)—, or [ka] is a divalent moiety selected from

[0259] In some embodiments, X 1 , X 6 , and X 7 Each of X is independently a covalent bond. 1 , X 6 , and X 7 Each of X is independently -CH-.1 , X 6 , and X 7 Each of X is independently -CR-. 1 , X 6 , and X 7 Each of X is independently -C(O)-. 1 , X 6 , and X 7 Each of X is independently -C(S)-. 1 , X 6 , and X 7 Each of X is independently -CH(R)-. 1 , X 6 , and X 7 Each of X is independently -CH(CF3)-. 1 , X 6 , and X 7 Each of X is independently -P(O)(OR)-. 1 , X 6 , and X 7 Each of X is independently -P(O)(R)-. 1 , X 6 , and X 7 Each of X is independently -P(O)NR-. 1 , X 6 , and X 7 Each of X is independently -S(O)-. 1 , X 6 , and X 7 Each of X is independently -S(O)-. 1 , X 6 , and X 7 Each of the [ka] is.

[0260] In some embodiments, X1 , X 6 , and X 7 are each independently selected from those depicted in Table 1 below.

[0261] X, as defined above and described herein; 2 is a carbon atom, a nitrogen atom, or a silicon atom. 2 is a carbon atom or a silicon atom.

[0262] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom. In some embodiments, X 2 is a nitrogen atom.

[0263] In some embodiments, X 2 is selected from those illustrated in Table 1 below.

[0264] X, as defined above and described herein; 3 and X 5 are each independently a divalent moiety selected from -CH2-, -CR2-, -NR-, -CF2-, -CHF-, -S-, -CH(R)-, -SiR2-, or -O-.

[0265] In some embodiments, X 3 and X 5 Each of X is independently -CH-. 3 and X 5 Each of X is independently -CR-. 3 and X 5 Each of X is independently -NR-. 3 and X 5 Each of X is independently -CF-. 3 and X 5Each of X is independently -CHF-. 3 and X 5 Each of X is independently -S-. 3 and X 5 Each of X is independently -CH(R)-. 3 and X 5 Each of X is independently -SiR-. 3 and X 5 Each of is independently -O-.

[0266] In some embodiments, X 3 and X 5 are each independently selected from those depicted in Table 1 below.

[0267] X, as defined above and described herein; 4 teeth, [ka] is a trivalent moiety selected from

[0268] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] In some embodiments, X 4 teeth, [ka] is.

[0269] In some embodiments, X 4 is selected from those illustrated in Table 1 below.

[0270] R as defined above and described herein 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 Aliphatic or R 1 and X 1 Or X 4 together with the atoms 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, and sulfur.

[0271] 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 1In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -P(O)(OR). In some embodiments, R 1 is -P(O)(NR2)OR. In some embodiments, R 1 is —P(O)(NR) . In some embodiments, R 1 is —Si(OH)R. In some embodiments, R 1 is —Si(OH)(R). In some embodiments, R 1 is —Si(R). In some embodiments, R 1 is replaced by C 1~4 In some embodiments, R 1 and X 1 or X 4 together with the atoms 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, and sulfur.

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

[0273] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group, and the optionally substituted group is C 1~6Selected 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, 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, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0274] 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 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.

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

[0276] R as defined above and described herein 2 and R 3a each independently represents hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -Si(OH)2R, -Si(OH)R2, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O) R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -OC(O)R, -OC(O)NR2, -O P(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N (R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0277] In some embodiments, R 2 and / or R 3a is hydrogen. In some embodiments, R 2 and / or R 3a is deuterium. In some embodiments, R 2 and / or R 3a Ha-R 6 In some embodiments, R 2 and / or R 3a is halogen. In some embodiments, R 2 and / or R 3a is -CN. In some embodiments, R 2 and / or R 3a is —NO. In some embodiments, R 2 and / or R 3a In some embodiments, R 2 and / or R 3a is —Si(OH)R. In some embodiments, R 2 and / or R 3a is —Si(OH)R. In some embodiments, R 2 and / or R 3a In some embodiments, R2 and / or R 3a is -NR2. In some embodiments, R 2 and / or R 3a is -SiR. In some embodiments, R 2 and / or R 3a is —S(O)R. In some embodiments, R 2 and / or R 3a is —S(O)NR. In some embodiments, R 2 and / or R 3a is -S(O)R. In some embodiments, R 2 and / or R 3a is —C(O)R. In some embodiments, R 2 and / or R 3a is —C(O)OR. In some embodiments, R 2 and / or R 3a is —C(O)NR. In some embodiments, R 2 and / or R 3a is —C(O)N(R)OR. In some embodiments, R 2 and / or R 3a is —C(R)N(R)C(O)R. In some embodiments, R 2 and / or R 3a is —C(R)N(R)C(O)NR. In some embodiments, R 2 and / or R 3a is -OC(O)R. In some embodiments, R 2 and / or R 3a is —OC(O)NR. In some embodiments, R 2 and / or R 3a is -OP(O)R. In some embodiments, R 2 and / or R 3a is -OP(O)(OR). In some embodiments, R 2 and / or R 3ais -OP(O)(OR)NR. In some embodiments, R 2 and / or R 3a is -OP(O)(NR)-. In some embodiments, R 2 and / or R 3a is —N(R)C(O)OR. In some embodiments, R 2 and R 3a is independently —N(R)C(O)R. In some embodiments, R 2 and / or R 3a is —N(R)C(O)NR. In some embodiments, R 2 and / or R 3a is -NP(O)R. In some embodiments, R 2 and / or R 3a is —N(R)P(O)(OR). In some embodiments, R 2 and / or R 3a is —N(R)P(O)(OR)NR. In some embodiments, R 2 and / or R 3a is —N(R)P(O)(NR). In some embodiments, R 2 and / or R 3a is -N(R)S(O)R.

[0278] In some embodiments, R 2 and R 3a is independently —OH. In some embodiments, R 2 and R 3a is independently -NH. In some embodiments, R 2 and R 3a is independently —CH 2 NH 2 . In some embodiments, R 2 and R 3a is independently -CHNHCOMe. In some embodiments, R 2 and R 3a is independently -CHNHCONHMe. In some embodiments, R 2 and R3a is independently -NHCOMe. In some embodiments, R 2 and R 3a is independently -NHCONHEt. In some embodiments, R 2 and R 3a is independently -SiMe. In some embodiments, R 2 and R 3a is independently —SiMeOH. In some embodiments, R 2 and R 3a is independently —SiMe(OH). In some embodiments, R 2 and / or R 3a teeth [ka] In some embodiments, R 2 and / or R 3a is Br. In some embodiments, R 2 and / or R 3a is Cl. In some embodiments, R 2 and / or R 3a is F. In some embodiments, R 2 and / or R 3a is Me. In some embodiments, R 2 and / or R 3a is -NHMe. In some embodiments, R 2 and / or R 3a is -NMe2. In some embodiments, R 2 and / or R 3a is -NHCO2Et. In some embodiments, R 2 and / or R 3a is -CN. In some embodiments, R 2 and / or R 3a is -CHPh. In some embodiments, R 2 and / or R 3a is -NHCO2tBu. In some embodiments, R2 and / or R 3a is -CO2tBu. In some embodiments, R 2 and / or R 3a is -OMe. In some embodiments, R 2 and / or R 3a is -CF3.

[0279] In some embodiments, R 2 and R 3a is selected from those illustrated in Table 1 below.

[0280] R as defined above and described herein 3 represents hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R )C(O)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O)2NR2, -N(R)P(O)(OR)2, -N(R)P(O )(OR)NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, or -Si(R)3.

[0281] 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 3In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)NR. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is —C(O)R. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —C(O)NR. In some embodiments, R 3 is —C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is —OC(O)NR. In some embodiments, R 3 is -OP(O)(OR). In some embodiments, R 3 is -OP(O)(NR). In some embodiments, R 3 is -OP(O)(OR)NR. In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)OR. In some embodiments, R 3 is —N(R)C(O)NR. In some embodiments, R 3 is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R 3 is —N(R)P(O)(OR)NR. In some embodiments, R 3 is -P(O)(OR). In some embodiments, R 3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R 3 is -Si(R)3.

[0282] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0283] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0284] 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.

[0285] 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, R4 is —S(O)R. In some embodiments, R 4 is —S(O)NR. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is —C(O)R. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —C(O)NR. In some embodiments, R 4 is —C(O)N(R)OR. In some embodiments, R 4 is -OC(O)R. In some embodiments, R 4 is —OC(O)NR. In some embodiments, R 4 is —N(R)C(O)OR. In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)NR. In some embodiments, R 4 is —N(R)S(O)R. In some embodiments, R 4 is -P(O)(OR). In some embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0286] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0287] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0288] R as defined above and described herein 5is hydrogen, deuterium, optionally substituted C 1~4 It is aliphatic, or -CN.

[0289] 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.

[0290] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0291] 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, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0292] 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, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0293] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0294] As generally defined above, each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1~4 Aliphatic or R 1 and X 1 Or X 3 and together with the atoms between them form a 5- to 7-membered, saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R on the same carbon 7 The groups may optionally be joined together with the atoms between them to form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R on adjacent carbon atoms may form a heterocyclic ring. 7 The groups, optionally taken together with the atoms between them, form a 3- to 7-membered, saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 7- to 13-membered, saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0295] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is halogen. In some embodiments, R7 is -CN. In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 is -S(O)R. In some embodiments, R 7 is —S(O)R. In some embodiments, R 7 is -NR2. In some embodiments, R 7 is —Si(R). In some embodiments, R 7 is -P(O)(R). In some embodiments, R 7 is -P(O)(OR). In some embodiments, R 7 is -P(O)(NR2)OR. In some embodiments, R 7 is —P(O)(NR) . In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is replaced by C 1~4 In some embodiments, R 7 and X 1 or X 3 and together with the atoms between them form a 5- to 7-membered, saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R on the same carbon 7 The groups, optionally taken together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on adjacent carbon atoms may be present. 7The groups, optionally taken together with the atoms between them, form a 3- to 7-membered, saturated, partially unsaturated, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R on adjacent carbon atoms 7 The groups, optionally taken together with the atoms between them, form a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0296] In some embodiments, R 7 is hydrogen, halogen, -CN, -OR, -NR2, or C 1~4 In some embodiments, R 7 is hydrogen, halogen, -CN, or C 1~4 In some embodiments, R 7 is fluoro. In some embodiments, two R 7 The groups, optionally taken together with the atoms between them, form a 3- or 4-membered spiro-fused ring.

[0297] In some embodiments, R 7 is selected from those illustrated in Table 1 below.

[0298] As defined above and described herein, ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from:

[0299] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0300] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0301] In some embodiments, ring A is selected from those depicted in Table 1 below.

[0302] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0303] In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a fused 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring B is a fused 5- to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0304] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0305] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0306] As defined above and described herein, Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0307] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0308] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0309] In some embodiments, ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0310] In some embodiments, ring C is [ka] is selected from.

[0311] In some embodiments, ring C is [ka] is selected from.

[0312] In some embodiments, ring C is selected from those depicted in Table 1 below.

[0313] As defined above and described herein, Ring D is a ring selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0314] In some embodiments, ring D is a 6- to 10-membered aryl. In some embodiments, ring D is a 6- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0315] In some embodiments, Ring D is quinoline. In some embodiments, Ring D is isoquinoline. In some embodiments, Ring D is imidazo[1,2-a]pyridine.

[0316] In some embodiments, ring D is selected from those depicted in Table 1 below.

[0317] As defined above and described herein, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of rings E, F, and G is independently optionally further substituted with 1 to 2 oxo groups.

[0318] In some embodiments, one or more of ring E, ring F, and ring G is a 6-membered aryl. In some embodiments, one or more of ring E, ring F, and ring G is a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more of ring E, ring F, and ring G is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, one or more of ring E, ring F, and ring G is independently a fused ring selected from a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, one or more of ring E, ring F, and ring G is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more of ring E, ring F, and ring G are optionally further substituted with 1 to 2 oxo groups.

[0319] In some embodiments, ring E, ring F, and ring G are selected from those depicted in Table 1 below.

[0320] As defined above and described herein, Ring H is a 7- to 9-membered saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, wherein Ring E is optionally further substituted with 1 to 2 oxo groups.

[0321] In some embodiments, Ring H is a 7- to 9-membered saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, wherein Ring H is optionally further substituted with 1 to 2 oxo groups.

[0322] In some embodiments, ring E and ring H are selected from those depicted in Table 1 below.

[0323] As defined above and described herein, each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0324] In some embodiments, each of ring I and ring J is independently a 6-membered heteroaryl. In some embodiments, each of ring I and ring J is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, each of ring I and ring J is independently a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0325] As defined above and described herein, ring K is a 5-12 (e.g., 6-12) membered saturated or partially unsaturated fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, wherein ring H is optionally further substituted with 1 to 2 oxo groups.

[0326] In some embodiments, ring K is a fused ring selected from a 5- to 12-membered (e.g., 6- to 12-membered) saturated or partially unsaturated carbocyclyl. In some embodiments, ring K is a 5- to 12-membered (e.g., 6- to 12-membered) saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, ring K is a fused 5- to 6-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

[0327] In some embodiments, ring I, ring J, and ring K are selected from those depicted in Table 1 below.

[0328] As defined above and described herein, ring M is [ka] is selected from.

[0329] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] is.

[0330] In some embodiments, ring M is selected from those depicted in Table 1 below.

[0331] As defined above and described herein, L 1 is a covalent bond, or C 1~3 a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-;

[0332] In some embodiments, L 1is a covalent bond. In some embodiments, L 1 is C 1~3 In some embodiments, L 1 is -CH-. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D)2-. In some embodiments, L 1 is -CHCH-. In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L is -NMe-. 1 In some embodiments, L is -NEt-. 1 is -CHNR-. In some embodiments, L 1 or -O-. In some embodiments, L 1 is —CH2O—. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1 is —C(O)O—. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is —S(O)—. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -NRS(O)-. In some embodiments, L 1 is -S(O)NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is -C(O)NR-.

[0333] In some embodiments, ring L 1 is selected from those illustrated in Table 1 below.

[0334] As defined above and described in embodiments herein, [ka] is a single or double bond.

[0335] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0336] In some embodiments, [ka] is selected from those illustrated in Table 1 below.

[0337] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0338] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[0339] In some embodiments, m is selected from those depicted in Table 1 below.

[0340] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0341] 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.

[0342] In some embodiments, n is selected from those depicted in Table 1 below.

[0343] As defined above and described herein, p is 0 or 1.

[0344] In some embodiments, p is 0. In some embodiments, p is 1.

[0345] In some embodiments, p is selected from those depicted in Table 1 below.

[0346] As defined above and described herein, q is 0, 1, 2, 3, or 4.

[0347] 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.

[0348] In some embodiments, q is selected from those depicted in Table 1 below.

[0349] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0350] In certain embodiments, the present invention provides that the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby representing a sequence of Formula Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7, Ii-8, Ii-9, Ii-10, Ii-11, Ii-12, Ii-13, Ii-14, Ii-15, Ii-16, Ii-17, or Ii-18, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X is selected from -CR2-, -O-, -S-, -S(O)-, -S(O)2-, and -NR-; 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, carbocyclic, or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same atom, optionally taken together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Y and Z are independently selected from -CR= and -N=; Ring W is a fused ring selected from benzo and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1 and R 2 is independently an optionally substituted monocyclic or bicyclic ring selected from phenyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 and R 4 are independently hydrogen and C 1~6 alkyl; R5 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 is selected from hydrogen, —C(O)R, —C(O)OR, and —C(O)NR; R 7 is hydrogen and R A Selected from; Each R A independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 8 is -C(O)R and R A Selected from; R 9 is a mono-, bis-, or tri-substituent on ring W, where each of the substituents is independently selected from halogen and optionally substituted C 1~6 selected from aliphatic; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 11 is -C(O)OR or -C(O)NR2; R 12 and R 13 are independently hydrogen and R A Select from or: R 12 and R 13optionally taken together with the atoms therebetween to form an optionally substituted 3- to 8-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 14 is R A and; R 15 is -CN; R 16 is R A ,-OR,-(CR2) 0~6 -C(O)R, -(CR2) 0~6 -C(O)OR, -(CR2) 0~6 -C(O)NR2, -(CR2) 0~6 -S(O)2R, -(CR2) 0~6 -N(R)S(O)2R, -(CR2) 0~6 -S(O)2NR2; R 17 is -(CR2) 0~6 -C(O)NR2; R 18 and R 19 are independently hydrogen and R A Selected from; R 20 and R 21 are independently hydrogen, R A , halogen, and -OR, or R 20 and R 21 optionally taken together with the atoms therebetween to form a fused 5- to 7-membered partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 22 , R 23 , R 25 , and R 27 are independently hydrogen, R A, halogen, —C(O)R, —C(O)OR, —C(O)NR2, —NR2, —OR, —S(O)R, —S(O)2R, —S(O)2NR2; R 24 , R 26 , and R 28 are independently hydrogen, R A , —C(O)R, —C(O)OR, —C(O)NR2, —S(O)R, —S(O)2R, and —S(O)2NR2; R 1’ and R 2’ are independently selected from halogen, —C≡CR, —CN, —CF3, and —NO2; R 3’ is -OR; R 4’ , R 5’ , R 6’ are independently hydrogen, halogen, or R A , -CN, -CF3, -NR2, -OR, -SR, and -S(O)2R; R 7’ is a mono-, bis-, or tri-substituent, wherein each of the substituents is independently selected from halogen; R 8’ is a mono-, bis-, or tri-substituent, where each of the substituents is independently hydrogen, halogen, R A , -CN, -C≡CR, -NO2, and -OR; R 9’ is R A and; Z 1 is selected from hydrogen, halogen, and -OR; R 10’ and R 11’ are independently hydrogen and R A Selected from; R 12’ is selected from —C(O)R, —C(O)OR, —C(O)NR, —OR, —S(O)R, —S(O)NR, and —S(O)R; and R 1″ is hydrogen and R A is selected from.

[0351] In certain embodiments, the present invention provides a method for the preparation of a nucleotide sequence of Formula Ii-19, Ii-20, or Ii-21, respectively, wherein the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby providing a nucleotide sequence of Formula Ii-19, Ii-20, or Ii-21, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and R 1″ is hydrogen and R A Selected from; Each R A independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 and R 13 are each independently hydrogen and R A Select from or: R 12 and R 13 optionally taken together with the atoms therebetween to form an optionally substituted 4- to 8-membered, saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; A 5 is -C(R 18a )= and -N=; A 6is -C(R 18b )= and -N=; A 7 is -C(R 18d )= and -N=; R 18a , R 18b , R 18c , and R 18d are each independently hydrogen, halogen, or R A , and -OR; 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 carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring W is an optionally substituted fused ring selected from benzo and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q 1 is an optionally substituted divalent group selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl, and heterocyclenyl.

[0352] In certain embodiments, the invention provides an IAP E3 ubiquitin ligase binding moiety, whereby the LBM is an IAP E3 ubiquitin ligase binding moiety, represented by formula Ij-1, Ij-2, Ij-3, or Ij-4, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and the variable R 1 , R 2 , R3 , R 4 , R 5 , R 6 , and R 7 each as defined and described in WO 2017 / 011590 and US 2017 / 0037004, each of which is incorporated by reference in its entirety.

[0353] In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is an IAP binding moiety, whereby the compound has the formula Ik-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and the variables W, Y, Z, R 1 , R 2 , R 3 , R 4 , and R 5 each as described and defined in WO 2014 / 044622, US 2015 / 0225449, WO 2015 / 071393, and US 2016 / 0272596, each of which is incorporated by reference in its entirety.

[0354] In certain embodiments, the present invention provides compounds of formula I-DB: [ka] or a pharmaceutically acceptable salt thereof, wherein: A TBM is a target binding moiety capable of binding to a targeted protein(s). L is a bivalent moiety that links the TBM to the DBM; and DBM is a DCAF1 binding moiety capable of binding to DCAF1 protein.

[0355] In certain embodiments, the present invention provides a compound wherein DBM has formula Ik-2-a: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and Ring T is phenyl, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring U is phenyl, a 4- to 7-membered partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring V is phenylenyl, a 4- to 10-membered partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y 1 is C 1~3 a hydrocarbon chain, wherein each methylene is optionally replaced by -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-; R a is replaced by C 1~6 Aliphatic or [ka] and; R b is hydrogen, optionally substituted C 1~6 aliphatic, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Ra and R b optionally taken together with the atoms between them, form an optionally substituted 9- to 10-membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: When Y is -C(NR)-, R b optionally taken together with R and the atoms therebetween of -C(NR)- to form a 5- to 7-membered partially unsaturated heterocyclyl having 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the two nitrogen atoms already mentioned in the formed heterocyclyl; R c is -CR2CONR2, a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R d is hydrogen, or: R c If -CR2CONR2, then R d is a group consisting of one R in -CR2CONR2 and atoms between them as needed, and R d forms a 5- to 7-membered saturated or partially unsaturated heterocyclyl having, in addition to the nitrogen atom to which it is attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R t , R u , and R v are each independently hydrogen, oxo, R A, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C (O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O) selected from (NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2, -P(O)(OR)NR2, and -P(O)(NR2)2; Each R A independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated, carbocyclic, or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, optionally taken together with atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to the atom to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; s is 0 or 1; and each of t, u, and v is independently 0, 1, 2, 3, or 4; Here, DBM is [ka] with further substitutions as necessary, where [ka] is the warhead group.

[0356] In certain embodiments, the present invention provides a compound wherein DBM has formula Ik-2-b: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and Ring W is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring X is phenylenyl, 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclolenyl, or heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring Y is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclolenyl, or heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring Z is a 9- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from phenyl, naphthyl, nitrogen, oxygen, and sulfur, or a 5- to 13-membered monocyclic, bicyclic, or tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R w , R x , R y , and R z are each independently hydrogen, oxo, R A , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2 )2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2, -P(O)(OR)NR2, and -P(O)(NR2)2, or: R on the ring X x group and R y the group or ring Y, together with the atoms between them, optionally form a 5- to 8-membered saturated or partially unsaturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R A independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each 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, carbocyclic, or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, optionally taken together with atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to the atom to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X 1 and X 2 each independently is a covalent bond, a spiro fusion between ring X and ring Y, -CR2-, -CR(OR)-, -CRF-, -CF2-, -NR-, -O-, -S-, or -S(O)2-; s is 0 or 1; and each of w, x, y, and z is independently 0, 1, 2, 3, or 4; Here, DBM is [ka] with further substitutions as necessary, where [ka] is the warhead base.

[0357] As described above and defined herein, Ring T is phenyl, a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0358] In some embodiments, Ring T is phenyl. In some embodiments, Ring T is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring T is a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0359] In some embodiments, Ring T is cyclohexyl, cyclohexenyl, isothiazolyl, phenyl, or pyridyl.

[0360] In some embodiments, ring T is as depicted in the compounds of Table 1 below.

[0361] As described above and defined herein, Ring U is phenyl, a 4- to 7-membered partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0362] In some embodiments, Ring U is phenyl. In some embodiments, Ring U is a 4- to 7-membered partially unsaturated carbocyclyl. In some embodiments, Ring U is a 4- to 7-membered partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring U is a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0363] In some embodiments, Ring U is cyclobutyl, azetinyl, cyclohexyl, cyclohexenyl, tetrahydro-2H-pyranyl, pyrrolidinyl, 4,5-dihydro-1H-pyrazolyl, piperidinyl, phenyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, benzimidazolyl, pyrazolo[1,5-a]pyridyl, or [1,2,4]triazolo[1,5-a]pyridyl.

[0364] In some embodiments, ring U is as depicted in the compounds of Table 1 below.

[0365] As described above and defined herein, Ring V is phenylenyl, a 4- to 10-membered partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0366] In some embodiments, Ring V is phenylenyl. In some embodiments, Ring V is a 4- to 10-membered partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring V is a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0367] In some embodiments, Ring V is cyclobutylenyl, azetinylenyl, cyclopentylenyl cyclohexyl, phenylenyl, pyrrolilenyl, imidazolylenyl, pyrazolilenyl, 1,2,3-triazolilenyl, 1,2,4-triazolilenyl, pyridylenyl, indazolyl, 1,2,3,6-tetrahydropyridinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridyl, benzimidazolyl, 3,4-dihydroquinolinyl, or 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridyl.

[0368] In some embodiments, ring V is as depicted in the compounds of Table 1 below.

[0369] As described above and defined herein, Ring W is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0370] In some embodiments, ring W is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, ring W is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0371] In some embodiments, ring W is cyclopropyl, cyclobutyl, azetinyl, pyrrolidinyl, cyclohexyl, piperidinyl, piperazinyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, morpholinyl, piperzinyl, 2,7-diazaspiro[3.5]nonanyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, or 2-oxa-5-azabicyclo[2.2.2]octanyl.

[0372] In some embodiments, ring W is as depicted in the compounds of Table 1 below.

[0373] As described above and defined herein, Ring X is phenylenyl, a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclolenyl, or heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0374] In some embodiments, ring X is phenylenyl. In some embodiments, ring X is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl. In some embodiments, ring X is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring X is a 5- to 9-membered, monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0375] In some embodiments, ring X is phenylenyl, imidazolylenyl, pyrazolilenyl, oxazolilenyl, thiazolylenyl, 1,2-thiazinanylenyl, pyridylenyl, pyridazinylenyl, pyrimidinylenyl, 2,6-diazaspiro[3.5]nonanylenyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridylenyl, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridylenyl, 1H-pyrrolo[2,3-b]pyridylenyl, 3H-imidazo[4,5-b]pyridylenyl, 9H-purinylenyl, 1,2,3,4-tetrahydro-1,8-naphthyridinylenyl, or 1,2,3,4-tetrahydro-1,6-naphthyridinylenyl.

[0376] In some embodiments, ring X is as depicted in the compounds of Table 1 below.

[0377] As described above and defined herein, Ring Y is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclolenyl, or heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0378] In some embodiments, ring Y is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, ring Y is a 3- to 11-membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0379] In some embodiments, ring Y is cyclohexylenyl, azetidinylenyl, pyrrolidinylenyl, imidazolylenyl, piperidinylenyl, piperzinylenyl, azepanylenyl, 8-azabicyclo[3.2.1]octanylenyl, 2-azabicyclo[3.2.1]octanylenyl, 2-azabicyclo[3.2.2]nonanylenyl, octahydro-1H-pyrrolo[3,2-b]pyridylenyl, decahydro-1,5-naphthyridinylenyl, 9-azabicyclo[3.3.1]nonanylenyl, 5-azaspiro[3.5]nonanylenyl, 2-oxa-5-azaspiro[3.5]nonanylenyl, or 2,6-diazaspiro[3.5]nonanylenyl.

[0380] In some embodiments, ring Y is as depicted in the compounds of Table 1 below.

[0381] As described above and defined herein, ring Z is a 9- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from phenyl, naphthyl, nitrogen, oxygen, and sulfur, or a 5- to 13-membered monocyclic, bicyclic, or tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0382] In some embodiments, ring Z is phenyl. In some embodiments, ring Z is naphthyl. In some embodiments, ring Z is a 9- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Z is a 5- to 13-membered monocyclic, bicyclic, or tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0383] In some embodiments, ring Z is 1,2,3-triazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, pyrazolo[1,5-a]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridinyl, naphthyl, quinolinyl, isoquinolinyl, 1,6 naphthyridinyl, phthalazinyl, quinazolinyl, 2,7 naphthyridinyl, or tetrazolo[1,5-a]quinoxalinyl.

[0384] In some embodiments, ring Z is as depicted in the compounds of Table 1 below.

[0385] As described above and defined herein, R a is replaced by C 1~6 Aliphatic or [ka] is.

[0386] In some embodiments, R a is replaced by C 1~6 In some embodiments, R a teeth, [ka] is.

[0387] In some embodiments, ring R a is methyl.

[0388] In some embodiments, ring R a are as illustrated in the compounds in Table 1 below.

[0389] As described above and defined herein, R b is hydrogen, optionally substituted C 1~6 aliphatic, phenyl, or 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R a and R b optionally taken together with the atoms between them, form an optionally substituted 9- to 10-membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or when Y is -C(NR)-, R b optionally taken together with R and the atoms between them of -C(NR)- to form a 5- to 7-membered partially unsaturated heterocyclyl having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, in addition to the two nitrogen atoms already mentioned in the formed heterocyclyl.

[0390] In some embodiments, R b is hydrogen. In some embodiments, R b is hydrogen, optionally substituted C 1~6 In some embodiments, R b is hydrogen and phenyl. In some embodiments, R b is hydrogen and is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a and R boptionally taken together with the atoms between them, form an optionally substituted 9- to 10-membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Y is -C(NR)-, R b optionally taken together with R and the atoms between them of -C(NR)- to form a 5- to 7-membered partially unsaturated heterocyclyl having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, in addition to the two nitrogen atoms already mentioned in the formed heterocyclyl.

[0391] In any embodiment, R b is methyl, cyclopropyl, phenyl, -CO2H, -CH2cyclopropyl, -CH2OH, -CH2OMe, or -CH2CO2H.

[0392] In some embodiments, ring R b are as illustrated in the compounds in Table 1 below.

[0393] As described above and defined herein, R c is -CR2CONR2, a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0394] In some embodiments, R c is -CR2CONR2. In some embodiments, R c is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. c is a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. cis a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0395] In some embodiments, R c is -CH2CONH2, -CH(Me)CONH2, -CH2CONHMe, -CH2CONHEt, -CH2CONHCH2Ph, -CH2CONHcyclopropyl, pyrrolidin-2-onyl, piperidin-2-onyl, or isoxazolyl.

[0396] In some embodiments, ring R c are as illustrated in the compounds in Table 1 below.

[0397] As described above and defined herein, R d is hydrogen or R c If -CR2CONR2, then R d is a group consisting of one R in -CR2CONR2 and atoms between them as needed, and R d forms a 5- to 7-membered saturated or partially unsaturated heterocyclyl having, in addition to the nitrogen atom to which it is attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0398] In some embodiments, R d is hydrogen.

[0399] In some embodiments, ring R d are as illustrated in the compounds in Table 1 below.

[0400] As described above and defined herein, R t , R u , R v , R w , R x , R y , and R z are each independently hydrogen, oxo, R A, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O) NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2 , -NRC(O)OR, -NRC(O)R, -NRC(O)N(R), -NRS(O)R, -NP(O)R, -NRP(O)(OR), -NRP(O)(OR)NR, -NRP(O)(NR), -P(O)R, -P(O)(OR), -P(O)(OR)NR, and -P(O)(NR), or R on ring X x group and R y The group or ring Y, together with the atoms between them, if necessary, form a 5- to 8-membered saturated or partially unsaturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0401] In some embodiments, R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z One or more of the A In some embodiments, R t , R u , R v , R w , Rx , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v, R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R zIn some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v, R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R zIn some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R t , R u , R v , R w , R x , R y , and R z In some embodiments, one or more of R on ring X is -P(O)(NR). x group and R y The group or ring Y, together with the atoms between them, form a 5- to 8-membered saturated or partially unsaturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0402] In some embodiments, R tis hydrogen, oxo, fluoro, chloro, —CN, methyl, —CONH 2 , —OH, or —OMe.

[0403] In some embodiments, R u is hydrogen, oxo, fluoro, chloro, -CN, methyl, -COH, -COMe, -CONH, -C(O)CHCH, -OH, -OMe, -CHCHF, -CHOMe, -CHCOH, -CHSOMe, -CHCHOH, -CHCHSOMe, -CHCHOMe, -NHC(O)CHCH, tetrazolyl, or N-methyltetrazolyl.

[0404] In some embodiments, R v is hydrogen, oxo, methyl, isopropyl, -CHcyclopropyl, -CHcyclopentyl, -CHcyclohexyl, -CHmorpholinyl, -CHPh, -CHthiazolyl, -CHpyrimidinyl, -CHCHOMe, -CHCHPh, -C(O)Me, -C(O)CHCH, -C(O)Ph, -C(O)pyrimidinyl, -NH, -NHC(O)CHCH, -CHNHC(O)CHCH, -CCNHC(O)CHCH, -NHcyclohexyl, -NHphenyl, or -NHpyrimidinyl.

[0405] In some embodiments, R w is hydrogen, oxo, fluoro, methyl, ethyl, n-propyl, b-butyl, -CH2CH2OMe, -C(O)CHCH2, -NHC(O)CHCH2, -N(Me)C(O)CHCH2, -CH2NHC(O)CHCH2, or [ka] is.

[0406] In some embodiments, R x is hydrogen, oxo, fluoro, chloro, methyl, —CF3, —CH2OH, —CN, —OH, —OMe, —NH2, or —N(Me)CH2CH2CH2N(Me)C(O)CHCH2.

[0407] In some embodiments, R y is hydrogen, oxo, fluoro, methyl, —CHF, —CHOH, —COH, —C(O)NH, —OH, —OMe, or —S(O)NH.

[0408] In some embodiments, R x and R y are joined by -CH2CH2- or -CH2CH2CH2-.

[0409] In some embodiments, R z is hydrogen, oxo, fluoro, chloro, -CN, methyl, isobutyl, -CF3, -CH2CF3, -CH2OH, -CH2CO2Me, -CH(OH)Me, -CH(NH2)cyclopropyl, -CH2Ph, -OH, -OMe, -OCF3, -OiPr, OPh, -NHC(O)Me, -NHC(O)CHCH2, -S(O)2NH2, 1,2,3-triazolyl, piperidinyl, N-methylpiperdinyl, phenyl, or pyridyl.

[0410] In some embodiments, R t , R u , R v , R w , R x , R y , and R z are as illustrated in the compounds in Table 1 below.

[0411] As described above and defined herein, each R A independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0412] In some embodiments, R A is replaced by C 1~6 In some embodiments, R A is optionally substituted phenyl. In some embodiments, R A is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R A is an optionally substituted saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R A is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0413] In some embodiments, R A is C 1~6 alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, R A is C 1~6 Haloalkyl (e.g., -CF3, -CHF2).

[0414] In any embodiment, R A are as illustrated in the compounds in Table 1 below.

[0415] As described above and defined herein, 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 carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom optionally taken together with atoms between them form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to the atom to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0416] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom, optionally combined with the atom between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to the atom to which they are attached, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0417] In any embodiment, R is as depicted in the compounds of Table 1 below.

[0418] X, as described above and defined herein 1 and X 2each is independently a covalent bond, -CR2-, -CR(OR)-, -CRF-, -CF2-, -NR-, -O-, -S-, or -S(O)2-.

[0419] In some embodiments, X 1 and / or X 2 is a covalent bond. In some embodiments, X 1 and / or X 2 is -CR2-. In some embodiments, X 1 and / or X 2 is -CR(OR)-. In some embodiments, X 1 and / or X 2 In some embodiments, X is -CRF-. 1 and / or X 2 In some embodiments, X is —CF—. 1 and / or X 2 is -NR-. In some embodiments, X 1 and / or X 2 is —O—. In some embodiments, X 1 and / or X 2 is -S-. In some embodiments, X 1 and / or X 2 is -S(O)2-.

[0420] In some embodiments, X 1 is a covalent bond, —NH—, or —NMe—.

[0421] In some embodiments, X 2represents a covalent bond, -CH2-, -CMe(OMe)-, -CMe(F)-, -CMe(CF3)-, cyclopropylenyl, difluorocyclopropylenyl, -NH-, -NMe-, -N(COMe)-, -N(CF3)-, -NEt-, -N(nPr)-, -N(nBu)-, -N(Ph)-, -N(3-pyridyl)-, -N(4-pyridyl)-, -N(SO2Me)-, -N(CH2CHF2)-, -N( CH2cyclopropyl)-, -N(CH2Ph)-, -N(CH2CONH2)-, -N(CH2SO2Me)-, -N(CH2CH2CHF2)-, -N(CH2CH2Ph)-, -N(CH2CH2CO2H)-, -N(CH2CH2CONH2)-, -N(CH2CH2CN)-, -N(CH2CH2OMe)-, -N(CH2CH2SO2Me)-, -O-, -S-, or -S(O)2-.

[0422] In any embodiment, X is as depicted in the compounds of Table 1 below.

[0423] As described above and defined herein, Y 1 is C 1~3 A hydrocarbon chain in which each methylene is optionally replaced with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-.

[0424] In some embodiments, Y 1 is C 1~3 A hydrocarbon chain in which each methylene is optionally replaced with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-.

[0425] In some embodiments, Y 1 is C 1~3 In some embodiments, Y is a hydrocarbon chain. 1 In some embodiments, Y is -CR-. 1 is -CR(OR)-. In some embodiments, Y 1is —C(O)—. In some embodiments, Y 1 is -C(NR)-. In some embodiments, Y 1 is -C(NOR)-. In some embodiments, Y 1 is -S(O)-. In some embodiments, Y 1 is -S(O)2-.

[0426] In some embodiments, Y 1 is —CH—, —CHC(O)—, —NHCHC(O)—, —CHCHC(O)—, —CHCH(OH)C(O)—, —C(O)—, —C(NH)—, —C(NOH)—, —S(O)—, or —S(O)—.

[0427] In any embodiment, Y 1 are as illustrated in the compounds in Table 1 below.

[0428] As described above and defined herein, s is 0 or 1.

[0429] In some embodiments, s is 0. In some embodiments, s is 1.

[0430] In any embodiment, s is as depicted in the compounds of Table 1 below.

[0431] As described above and defined herein, each of t, u, v, w, x, y, and z is independently 0, 1, 2, 3, or 4.

[0432] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0433] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[0434] In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4.

[0435] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0436] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0437] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4.

[0438] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4.

[0439] In any embodiment, t, u, v, w, x, y, and z are as depicted in the compounds of Table 1 below.

[0440] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] is.

[0441] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] In some embodiments, the DBM is [ka] is.

[0442] In certain embodiments, the present invention provides a compound of the formula: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0443] In certain embodiments, the present invention provides a compound of the formula: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0444] As defined above and described herein, DBM is [ka] with further substitutions as necessary, where [ka] is the warhead base.

[0445] In some embodiments, the warhead group is -L 2 -Y, L 2 is a covalent bond or a bivalent saturated or unsaturated, linear or branched C 1~8 is a hydrocarbon chain, L 2wherein one, two, or three methylene units are optionally replaced independently by cyclopropylene, -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SON(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-; Y is C optionally substituted with hydrogen, oxo, halogen, NO2 or CN. 1~6 a 3-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having an aliphatic or 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring containing 1-4 R e is substituted with a group, Each R e are independently -QZ, oxo, NO, halogen, CN, a suitable leaving group, or C optionally substituted with oxo, halogen, NO, or CN. 1~6 selected from aliphatic Q is a covalent bond or a bivalent saturated or unsaturated, straight or branched C 1~6 is a hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by -N(R)-, -S-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, or -SON(R)-; Z is hydrogen or C optionally substituted with oxo, halogen, NO or CN. 1~6 It is aliphatic.

[0446] In certain embodiments, L 2 is a covalent bond.

[0447] In certain embodiments, L 2 is a bivalent saturated or unsaturated, straight or branched C 1~8 In certain embodiments, L 2 is -CH2-.

[0448] In certain embodiments, L 2 is a covalent bond, —CH—, —NH—, —CHNH—, —NHCH—, —NHC(O)—, —NHC(O)CHOC(O)—, —CHNHC(O)—, —NHSO—, —NHSOCH—, —NHC(O)CHOC(O)—, or —SONH—.

[0449] In some embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 wherein one or two additional methylene units are independently replaced by -NRC(O)-, -C(O)NR-, -N(R)SO-, -SON(R)-, -S-, -S(O)-, -SO-, -OC(O)-, -C(O)O-, cyclopropylene, -O-, -N(R)-, or -C(O)-.

[0450] In certain embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 at least one methylene unit is replaced by -C(O)-, -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, or -C(O)O-; 2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0451] In some embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 At least one methylene unit of is replaced by -C(O)-, and L2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0452] As noted above, in certain embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond. Those skilled in the art will recognize that such double bond may be within the hydrocarbon chain backbone or may be "exo" to the backbone chain, thus forming an alkylidene group. For example, such L having an alkylidene branched chain may be 2 Groups include -CHC(=CH)CH-. Thus, in some embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one alkylidenyl double bond. 2 Groups include -NHC(O)C(=CH2)CH2-.

[0453] In certain embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 At least one methylene unit of L is replaced by -C(O)-. 2 -C(O)CH=CH(CH3)-, -C(O)CH=CHCH2NH(CH3)-, -C(O)CH=CH(CH3)-, -C(O)CH=CH-, -CH2C(O)CH=CH-, -CH2C(O)CH=CH(CH3)-, -CH2CH2 C(O)CH=CH-, -CH2CH2C(O)CH=CHCH2-, -CH2CH2C(O)CH=CHCH2NH(CH3)-, or -CH2CH2C(O)CH=CH(CH3)-, or -CH(CH3)OC(O)CH=CH-.

[0454] In certain embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 at least one methylene unit of is replaced by -OC(O)-.

[0455] In some embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 at least one methylene unit of is replaced by -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, or -C(O)O-; 2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. In some embodiments, L 2 is -CH2OC(O)CH=CHCH2-, -CH2-OC(O)CH=CH-, or -CH(CH=CH2)OC(O)CH=CH-.

[0456] In certain embodiments, L 2 is -NRC(O)CH=CH-, -NRC(O)CH=CHCH2N(CH3)-, -NRC(O)CH=CHCHO-, -CH2NRC(O)CH=CH-, -NRSO2CH=CH-, -NRSO2CH=CHCH2-, -NRC(O)(C=N2)C(O)-, -NRC(O)CH=CHCH2N(CH3)-, -NRSO2CH=CH-, -NRSO2CH=CHCH2-, -NRC(O)CH=CHCHO-, -NRC(O)C(=CH2)CH2-, -CH2NRC(O)-, -CH2NRC(O)CH=CH-, -CH2CH2NRC(O)-, or -CH2NRC(O)cyclopropylene-; and each R is independently hydrogen or an optionally substituted C 1~6 It is aliphatic.

[0457] In certain embodiments, L 2 -NHC(O)CH=CH-, -NHC(O)CH=CHCH2N(CH3)-, -NHC(O)CH=CHCH2O-, -CH2NHC(O)CH=CH-, -NHSO2CH=CH-, -NHSO2CH=CHCH2-, -NHC(O)(C=N2)C(O)-, -NHC(O)CH=CHCH2N(C H3)-, -NHSO2CH=CH-, -NHSO2CH=CHCH2-, -NHC(O)CH=CHCH2O-, -NHC(O)C(=CH2)CH2-, -CH2NHC(O)-, -CH2NHC(O)CH=CH-, -CH2CH2NHC(O)-, or -CH2NHC(O)cyclopropylene-.

[0458] In some embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one triple bond. 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one triple bond, and L 2 wherein one or two additional methylene units are independently optionally replaced by -NRC(O)-, -C(O)NR-, -S-, -S(O)-, -SO2-, -C(=S)-, -C(=NR)-, -O-, -N(R)-, or -C(O)-. 2 has at least one triple bond, and L 2 wherein at least one methylene unit is replaced by -N(R)-, -N(R)C(O)-, -C(O)-, -C(O)O-, or -OC(O)-, or -O-.

[0459] Exemplary L 2 Groups include -C≡C-, -C≡CCH2N(isopropyl)-, -NHC(O)C≡CCH2CH2-, -CH2-C≡C≡CH2-, -C≡CCH2O-, -CH2C(O)C≡C-, -C(O)C≡C-, or -CH2OC(=O)C≡C-.

[0460] In certain embodiments, L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 One methylene unit of L is replaced by cyclopropylene, 2 wherein one or two additional methylene units are independently replaced by -C(O)-, -NRC(O)-, -C(O)NR-, -N(R)SO-, or -SON(R)-. 2 Groups include -NHC(O)-cyclopropylene-SO2- and -NHC(O)-cyclopropylene-.

[0461] As generally defined above, Y is a C optionally substituted with hydrogen, oxo, halogen, NO or CN. 1~6 a 3-10 membered monocyclic or bicyclic saturated, partially unsaturated or aryl ring having an aliphatic or 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring comprising 1-4 R e groups, and each R e is -QZ, oxo, NO2, halogen, CN, an appropriate leaving group, or C 1~6 aliphatic, and Q is a covalent bond or a divalent saturated or unsaturated, straight or branched C 1~6 is a hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by -N(R)-, -S-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, or -SON(R)-; Z is hydrogen or a C(O) optionally substituted by oxo, halogen, NO2, or CN; 1~6 It is aliphatic.

[0462] In certain embodiments, Y is hydrogen.

[0463] In certain embodiments, Y is C optionally substituted with oxo, halogen, NO, or CN. 1~6 In some embodiments, Y is a C optionally substituted with oxo, halogen, NO, or CN. 2~6 In other embodiments, Y is alkenyl, optionally substituted with oxo, halogen, NO, or CN. 2~6 In some embodiments, Y is C 2~6 In other embodiments, Y is C 2~4 It is alkynyl.

[0464] In other embodiments, Y is C substituted with oxo, halogen, NO, or CN. 1~6 Such Y groups include —CHF, —CHCl, —CHCN, and —CHNO.

[0465] In certain embodiments, Y is a saturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and Y is selected from 1-4 R e groups, and each R e is as defined above and described herein.

[0466] In some embodiments, Y is a saturated 3-4 membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, and the ring contains one to two R e groups, and each R e is as defined above and described herein. Exemplary such rings are epoxide and oxetane rings, each ring containing one to two R e groups, and each R e is as defined above and described herein.

[0467] In another embodiment, Y is a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen, said ring containing 1-4 R e groups, and each Re is as defined above and described herein. Such rings include piperidine and pyrrolidine, where each ring contains 1 to 4 R e groups, and each R e is as defined above and described herein. In certain embodiments, Y is [ka] where each R, Q, Z, and R e is as defined above and described herein.

[0468] In some embodiments, Y is a saturated 3-6 membered carbocyclic ring, said ring containing 1-4 R e groups, and each R e is as defined above and described herein. In certain embodiments, Y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each ring is selected from 1 to 4 R e groups, and each R e is as defined above and described herein. In certain embodiments, Y is [ka] where R e is as defined above and described herein.

[0469] In certain embodiments, Y is cyclopropyl optionally substituted with halogen, CN, or NO 2 .

[0470] In certain embodiments, Y is a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring is e groups, and each R e is as defined above and described herein.

[0471] In some embodiments, Y is a partially unsaturated 3-6 membered carbocyclic ring, said ring containing 1-4 R e groups, and each R e is as defined above and described herein. In some embodiments, Y is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and each ring is selected from 1 to 4 R e groups, and each R e is as defined above and described herein. In certain embodiments, Y is [ka] where each R e is as defined above and described herein.

[0472] In certain embodiments, Y is a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring is e groups, and each R e is as defined above and described herein. In certain embodiments, Y is [ka] wherein each R and R e is as defined above and described herein.

[0473] In certain embodiments, Y is a 6-membered aromatic ring having 0-2 nitrogens, and the ring is e groups, and each R e The groups are as defined above and described herein. In certain embodiments, Y is phenyl, pyridyl, or pyrimidinyl, and each ring contains 1 to 4 R e groups, and each R e is as defined above and described herein.

[0474] In some embodiments, Y is [ka] wherein each R e is as defined above and described herein.

[0475] In another embodiment, Y is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring is e groups, and each R e The groups are as defined above and described herein. In some embodiments, Y is a 5-membered partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring containing 1-4 R e groups, and each R e The groups are as defined above and described herein. Exemplary such rings are isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, triazole, thiadiazole, and oxadiazole, each ring containing 1 to 3 R e groups, and each R e The groups are as defined above and described herein. In certain embodiments, Y is [ka] wherein each R and R e is as defined above and described herein.

[0476] In certain embodiments, Y is an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is e is substituted with an R eis as defined above and described herein. According to another aspect, Y is a 9-10 membered bicyclic, partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring containing 1-4 R e is substituted with an R e is as defined above and described herein. Exemplary such bicyclic rings include 2,3-dihydrobenzo[d]isothiazole, wherein the ring is a ring having 1 to 4 R e is substituted with an R e is as defined above and described herein.

[0477] As generally defined above, each R e The groups are independently -QZ, oxo, NO, halogen, CN, a suitable leaving group, or C optionally substituted with oxo, halogen, NO, or CN. 1~6 aliphatic, where Q is a covalent bond or a bivalent saturated or unsaturated, straight or branched C 1~6 is a hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by -N(R)-, -S-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, or -SON(R)-; Z is hydrogen or a C(O) optionally substituted by oxo, halogen, NO2, or CN; 1~6 It is aliphatic.

[0478] In certain embodiments, R e is C optionally substituted with oxo, halogen, NO2, or CN 1~6 In another embodiment, R e is oxo, NO2, halogen, or CN.

[0479] In some embodiments, R e is -QZ, where Q is a covalent bond and Z is hydrogen (i.e., R eis hydrogen). In other embodiments, R e is -QZ, where Q is a bivalent saturated or unsaturated, straight or branched C 1~6 In another embodiment, Q is a divalent linear or branched C alkyl group having at least one double bond, optionally replacing one or two methylene units of Q independently by -NR-, -NRC(O)-, -C(O)NR-, -S-, -O-, -C(O)-, -SO-, or -SO2-. 2~6 is a hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -S-, -O-, -C(O)-, -SO-, or -SO2-. e The Z portion of the group is hydrogen. In some embodiments, -QZ is -NHC(O)CH=CH2 or -C(O)CH=CH2.

[0480] In certain embodiments, each R e is independently selected from oxo, NO, CN, fluoro, chloro, —NHC(O)CH═CH, —C(O)CH═CH, —CHCH═CH, —C≡CH, —C(O)OCHCl, —C(O)OCHF, —C(O)OCHCN, —C(O)CHCl, —C(O)CHF, —C(O)CHCN, or —CHC(O)CH.

[0481] In certain embodiments, R e is a suitable leaving group, i.e., a group that undergoes nucleophilic displacement. A "suitable leaving group" is a chemical group that is easily displaced by an incoming desired chemical moiety, e.g., the thiol moiety of a desired cysteine. Suitable leaving groups are well known in the art and can be found, for example, in "Advanced Organic Chemistry," Jerry March, 5 thEd., pp. 351-357, John Wiley and Sons, NY. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).

[0482] In certain embodiments, -L 2 The following embodiments and combinations of -Y apply: (a)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 wherein one or two additional methylene units are independently replaced by -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, -C(O)O-, cyclopropylene, -O-, -N(R)-, or -C(O)-; and Y is hydrogen or a C group optionally substituted with oxo, halogen, NO2, or CN. 1~6 aliphatic, or (b)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 at least one methylene unit is replaced by -C(O)-, -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, or -C(O)O-;2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, -O-, -N(R)-, or -C(O)-, and Y is hydrogen or a C(O) optionally substituted with oxo, halogen, NO or CN. 1~6 aliphatic, or (c)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 At least one methylene unit of is replaced by -C(O)-, and L 2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, -O-, -N(R)-, or -C(O)-, and Y is hydrogen or a C(O) optionally substituted with oxo, halogen, NO or CN. 1~6 aliphatic, or (d)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 wherein at least one methylene unit is replaced by —C(O)—, and Y is hydrogen or C optionally substituted with oxo, halogen, NO or CN. 1~6 aliphatic, or (e)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one double bond, and L 2 wherein at least one methylene unit is replaced by -OC(O)-, and Y is hydrogen or C optionally substituted with oxo, halogen, NO or CN. 1~6 aliphatic, or (f)L 2is -NRC(O)CH=CH-, -NRC(O)CH=CHCH2N(CH3)-, -NRC(O)CH=CHCHO-, -CH2NRC(O)CH=CH-, -NRSO2CH=CH-, -NRSO2CH=CHCH2-, -NRC(O)(C=N2)-, -NRC(O)(C=N2)C(O)-, -NRC(O)CH=CHCH2N(CH3)-, -NRSO2CH=CH-, -NRSO2CH=CHCH2-, -NRC(O)CH=CHCHO-, -NRC(O)C(=CH2)CH2-, -CH2NRC(O)-, -CH2NRC(O)CH=CH-, -CH2CH2NRC(O)-, or -CH2NRC(O)cyclopropylene-; R is H or an optionally substituted C 1~6 aliphatic, Y is hydrogen or C optionally substituted with oxo, halogen, NO or CN; 1~6 aliphatic, or (g)L 2 -NHC(O)CH=CH-, -NHC(O)CH=CHCH2N(CH3)-, -NHC(O)CH=CHCH2O-, -CH2NHC(O)CH=CH-, -NHSO2CH=C H-, -NHSO2CH=CHCH2-, -NHC(O)(C=N2)-, -NHC(O)(C=N2)C(O)-, -NHC(O)CH=CHCH2N(CH3)-, -NHSO2CH =CH-, -NHSO2CH=CHCH2-, -NHC(O)CH=CHCHO-, -NHC(O)C(=CH2)CH2-, -CH2NHC(O)-, -CH2NHC(O)CH=CH-, -CH2CH2NHC(O)-, or -CH2NHC(O)cyclopropylene-, and Y is hydrogen or C optionally substituted with oxo, halogen, NO2, or CN. 1~6 aliphatic, or (h)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one alkylidenyl double bond, and L 2at least one methylene unit is replaced by -C(O)-, -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, or -C(O)O-; 2 wherein one or two additional methylene units are independently optionally replaced by cyclopropylene, -O-, -N(R)-, or -C(O)-, and Y is hydrogen or a C(O) optionally substituted with oxo, halogen, NO or CN. 1~6 aliphatic, or (i)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 has at least one triple bond, and L 2 wherein one or two additional methylene units are independently replaced by -NRC(O)-, -C(O)NR-, -N(R)SO-, -SON(R)-, -S-, -S(O)-, -SO-, -OC(O)-, or -C(O)O-; and Y is hydrogen or C optionally substituted with oxo, halogen, NO, or CN. 1~6 aliphatic, or (j)L 2 is -C≡C-, -C≡CCH2N(isopropyl)-, -NHC(O)C≡CCH2CH2-, -CH2-C≡C≡CH2-, -C≡CCH2O-, -CH2C(O)C≡C-, -C(O)C≡C-, or -CH2C(=O)C≡C-, and Y is hydrogen or C optionally substituted with oxo, halogen, NO2, or CN. 1~6 aliphatic, or (k)L 2 is a divalent straight or branched C 2~8 is a hydrocarbon chain, L 2 One methylene unit of L is replaced by cyclopropylene, 2wherein one or two additional methylene units are independently replaced by -NRC(O)-, -C(O)NR-, -N(R)SO2-, -SON(R)-, -S-, -S(O)-, -SO2-, -OC(O)-, or -C(O)O-, and Y is hydrogen or C optionally substituted with oxo, halogen, NO2, or CN. 1~6 aliphatic, or (l)L 2 is a covalent bond and Y is selected from: (i) C substituted with oxo, halogen, NO2 or CN 1~6 Alkyl, (ii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkenyl, or (iii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkynyl, or (iv) a saturated 3- to 4-membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, said ring being e groups, and each R e is as defined above and described herein), or (v) a saturated 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from oxygen or nitrogen, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (vi) [ka] [Wherein each R, Q, Z, and R e is as defined above and described herein], or (vii) a saturated 3- to 6-membered carbocyclic ring (the ring is substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (viii) a partially unsaturated 3- to 6-membered monocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (ix) a partially unsaturated 3- to 6-membered carbocyclic ring (the ring is e groups, and each R e is as defined above and described herein), or (x) [ka] [In the formula, each R e is as defined above and described herein], or (xi) a partially unsaturated 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e is as defined above and described herein), or (xii) [ka] [Wherein, each R and R e is as defined above and described herein], or (xiii) a 6-membered aromatic ring having 0 to 2 nitrogen atoms (the ring is e groups, and each R e groups are as defined above and described herein), or (xiv) [ka] [In the formula, each R e is as defined above and described herein], or (xv) a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring ise groups, and each R e groups are as defined above and described herein), or (xvi) [ka] [Wherein, each R and R e is as defined above and described herein], or (xvii) an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being e is substituted with an R e is as defined above and described herein), (m)L 2 is —C(O)— and Y is selected from: (i) C substituted with oxo, halogen, NO2 or CN 1~6 alkyl, or (ii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkenyl, or (iii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkynyl, or (iv) a saturated 3- to 4-membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, said ring being e groups, and each R e is as defined above and described herein), or (v) a saturated 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from oxygen or nitrogen, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (vi) [ka] [Wherein each R, Q, Z, and R e is as defined above and described herein], or (vii) a saturated 3- to 6-membered carbocyclic ring (the ring is substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (viii) a partially unsaturated 3- to 6-membered monocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (ix) a partially unsaturated 3- to 6-membered carbocyclic ring (the ring is e groups, and each R e is as defined above and described herein), or (x) [ka] [In the formula, each R e is as defined above and described herein], or (xi) a partially unsaturated 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e is as defined above and described herein), or (xii) [ka] [Wherein, each R and R e is as defined above and described herein], or (xiii) a 6-membered aromatic ring having 0 to 2 nitrogen atoms (the ring is e groups, and each R e groups are as defined above and described herein), or (xiv) [ka] [In the formula, each R e is as defined above and described herein], or (xv) a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e groups are as defined above and described herein), or (xvi) [ka] [Wherein, each R and R e is as defined above and described herein], or (xvii) an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being e is substituted with an R e is as defined above and described herein), (n)L 2 is —N(R)C(O)— and Y is selected from: (i) C substituted with oxo, halogen, NO2 or CN 1~6 alkyl, or (ii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkenyl, or (iii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkynyl, or (iv) a saturated 3- to 4-membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, said ring being e groups, and each R e is as defined above and described herein), or (v) a saturated 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from oxygen or nitrogen, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (vi) [ka] [Wherein each R, Q, Z, and R e is as defined above and described herein], or (vii) a saturated 3- to 6-membered carbocyclic ring (the ring is substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (viii) a partially unsaturated 3- to 6-membered monocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (ix) a partially unsaturated 3- to 6-membered carbocyclic ring (the ring is e groups, and each R e is as defined above and described herein), or (x) [ka] [In the formula, each R e is as defined above and described herein], or (xi) a partially unsaturated 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e is as defined above and described herein), or (xii) [ka] [Wherein, each R and R e is as defined above and described herein], or (xiii) a 6-membered aromatic ring having 0 to 2 nitrogen atoms (the ring is e groups, and each R e groups are as defined above and described herein), or (xiv) [ka] [In the formula, each R e is as defined above and described herein], or (xv) a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e groups are as defined above and described herein), or (xvi) [ka] [ka] [Wherein, each R and R e is as defined above and described herein], or (xvii) an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being e is substituted with an R e is as defined above and described herein), (o)L 2 is a bivalent saturated or unsaturated, straight or branched C 1~8 is a hydrocarbon chain and Y is selected from: (i) C substituted with oxo, halogen, NO2 or CN 1~6 Alkyl, (ii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkenyl, or (iii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkynyl, or (iv) a saturated 3- to 4-membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, said ring being e groups, and each R e is as defined above and described herein), or (v) a saturated 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from oxygen or nitrogen, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (vi) [ka] [Wherein each R, Q, Z, and R e is as defined above and described herein], or (vii) a saturated 3- to 6-membered carbocyclic ring (the ring is substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (viii) a partially unsaturated 3- to 6-membered monocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (ix) a partially unsaturated 3- to 6-membered carbocyclic ring (the ring is e groups, and each R e is as defined above and described herein), or (x) [ka] [In the formula, each R e is as defined above and described herein], or (xi) a partially unsaturated 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e is as defined above and described herein), or (xii) [ka] [Wherein, each R and R e is as defined above and described herein], or (xiii) a 6-membered aromatic ring having 0 to 2 nitrogen atoms (the ring is e groups, and each R e groups are as defined above and described herein), or (xiv) [ka] [In the formula, each R e is as defined above and described herein], or (xv) a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e groups are as defined above and described herein), or (xvi) [ka] [Wherein, each R and R e is as defined above and described herein], or (xvii) an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being eis substituted with an R e is as defined above and described herein), (p)L 2 is a covalent bond, —CH—, —NH—, —C(O)—, —CHNH—, —NHCH—, —NHC(O)—, —NHC(O)CHOC(O)—, —CHNHC(O)—, —NHSO—, —NHSOCH—, —NHC(O)CHOC(O)—, or —SONH—, and Y is selected from: (i) C substituted with oxo, halogen, NO2 or CN 1~6 alkyl, or (ii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkenyl, or (iii) C optionally substituted with oxo, halogen, NO2 or CN 2~6 alkynyl, or (iv) a saturated 3- to 4-membered heterocyclic ring having one heteroatom selected from oxygen or nitrogen, said ring being e groups, and each R e is as defined above and described herein), or (v) a saturated 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms selected from oxygen or nitrogen, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (vi) [ka] [Wherein each R, Q, Z, and R e is as defined above and described herein], or (vii) a saturated 3- to 6-membered carbocyclic ring (the ring is substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (viii) a partially unsaturated 3- to 6-membered monocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being substituted with 1 to 4 R e groups, and each R e is as defined above and described herein), or (ix) a partially unsaturated 3- to 6-membered carbocyclic ring (the ring is e groups, and each R e is as defined above and described herein), or (x) [ka] [In the formula, each R e is as defined above and described herein], or (xi) a partially unsaturated 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is e groups, and each R e is as defined above and described herein), or (xii) [ka] [Wherein, each R and R e is as defined above and described herein], or (xiii) a 6-membered aromatic ring having 0 to 2 nitrogen atoms (the ring is e groups, and each R e groups are as defined above and described herein), or (xiv) [ka] [In the formula, each R e is as defined above and described herein], or (xv) a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring ise groups, and each R e groups are as defined above and described herein), or (xvi) [ka] [Wherein, each R and R e is as defined above and described herein], or (xvii) an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being e is substituted with an R e is as defined above and described herein).

[0483] In certain embodiments, the Y group is selected from those set forth in Table 1A below, where each wavy line indicates a point of attachment to the remainder of the molecule. [Table 1A-1] [Table 1A-2] [Table 1A-3] [Table 1A-4] [In the formula, each R e are independently a suitable leaving group, NO, CN, or oxo.

[0484] In certain embodiments, the warhead group is -C≡CH, -C≡CCHNH(isopropyl), -NHC(O)C≡CCHCH, -CH-C≡C≡CH, -C≡CCHOH, -CHC(O)C≡CH, -C(O)C≡CH, or -CHC(=O)C≡CH. 1is selected from -NHC(O)CH=CH2, -NHC(O)CH=CHCH2N(CH3)2, or -CH2NHC(O)CH=CH2.

[0485] In certain embodiments, the warhead group is selected from those set forth in Table 1B below, where each wavy line indicates a point of attachment to the remainder of the molecule. [Table 1B-1] [Table 1B-2] [Table 1B-3] [Table 1B-4] [Table 1B-5] [In the formula, each R e are independently a suitable leaving group, NO, CN, or oxo.

[0486] In some embodiments, the warhead group Y is an isoxazoline compound or derivative that can be covalently attached to serine. In some embodiments, the warhead group Y is an isoxazoline compound or derivative described in WO2010135360, the entire contents of which are incorporated herein by reference. As will be appreciated by those skilled in the art, the isoxazoline compounds or derivatives described in WO2010135360 as the warhead group Y can be selected from the group consisting of L, L(R), ... 2 In some embodiments, the warhead group Y can be covalently linked to [ka] where G, R a , and R c teeth, [ka] [ka] [ka] [ka] [ka] is.

[0487] In certain embodiments, the present invention provides a compound wherein the LBM is a DCAF16 binding moiety, whereby the compound has formula Ik-2: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Zhang, X. et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 443804), each of which is incorporated herein by reference in its entirety, and wherein L and TBM are as defined above and as described in embodiments herein.

[0488] In certain embodiments, the present invention provides a compound wherein the LBM is an RNF114 binding moiety, whereby the compound has formula Ik-3: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, JNet al., bioRxiv (doi: https: / / doi.org / 10.1101 / 436998), each of which is incorporated herein by reference in its entirety, and wherein L and TBM are as defined above and as described in embodiments herein.

[0489] In certain embodiments, the present invention provides a compound wherein the LBM is an RNF4 binding moiety, whereby the compound has formula Ik-4: [ka] or a pharmaceutically acceptable salt thereof, as described and defined in Ward, CC, et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125), each of which is incorporated herein by reference in its entirety, and wherein L and TBM are as defined above and as described in embodiments herein.

[0490] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing a leukemia, ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described herein, and wherein variable R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 and each of X is as defined in WO 2019 / 099868, the entire contents of which are incorporated herein by reference; and [ka] is R as defined in WO 2018 / 237026 12 At the binding site of R 17 or R 16 is bound to, resulting in [ka] But R 12It takes the place of a substituent.

[0491] In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is a cereblon E3 ubiquitin ligase binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; thereby representing the formula Im-1, Im-2, or Im-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and as described in embodiments herein, and X 1 , X 2a , and X 3a each independently represents a covalent bond, —CH—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 4a and X 5a each independently is —CH—, —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; R 2 , R 3b , and R 4a each independently represents hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5a is hydrogen or C 1~6 It is aliphatic; Each R 6 independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 ...

Claims

1. Formula (II): 【Chemical 1226】 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II): TBM is a TYK binding moiety capable of binding to TYK2 protein; L is a divalent moiety connecting the TBM to ring A, where: Ring AAA is: 【Chemical 1227】 Selected from: R １００ is C １ ~C ６ alkyl or H; X １ は, shared combination, -CH ２ -CHCF ３ -, -SO ２ -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR ２ -, -C (O) -, -C (S) -, または 【Chemical 1228】 is a divalent moiety selected from X ２ is a carbon atom, a nitrogen atom, or a silicon atom; X ３ is a covalent bond, -CR ２ -, -NR-, -O-, -S-, or -Si(R) ２ - is a divalent moiety selected from R １ is absent or is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O) ２ R, -N(R) ２ , -P(O)(OR) ２ , -P(O)(NR ２ )OR, -P(O)(NR ２ ) ２ , —Si(OH) ２ R, -Si(OH)(R) ２ , -Si(R) ３ or optionally substituted C １～４ is aliphatic; Each R ２ are independently hydrogen, deuterium, -R ６ , halogen, -CN, -NO ２ , -OR, -SR, -N(R) ２ , -Si(R) ３ , -S(O) ２ R, -S(O) ２ N (R) ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ２ , -C(O)N(R)OR, -C(R) ２ N(R)C(O)R, -C(R) ２ N(R)C(O)N(R) ２ , -OC(O)R, -OC(O)N(R) ２ , -OP(O)R ２ , -OP(O)(OR) ２ , -OP(O)(OR)(NR ２ ), -OP(O)(NR ２ ) ２ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ２ , -N(R)S(O) ２ R, -NP(O)R ２ , -N(R)P(O)(OR) ２ , -N(R)P(O)(OR)(NR ２ ), -N(R)P(O)(NR ２ ) ２ , or -N(R)S(O) ２ R; Ring A is 【Chemical 1229】 【Chemical 1230】 【Chemical 1231】 , 6-membered aryl optionally substituted with one or more occurrences of halogen, and absent; Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ３ is hydrogen, halogen, -OR, -N(R) ２ or -SR; Each R ４ are independently hydrogen, —R ６ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O)2NR2, -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; R ５ is hydrogen, C １ ~C ４ aliphatic, or -CN; Each R ６ are independently optionally substituted groups selected from C1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L １ is a covalent bond, or C １ ~C ３ wherein one to two methylene units of the chain are independently —O—, —C(O)—, —C(S)—, —C(R) ２ -, -CH(R)-, -C(F) ２ -, -N(R)-, -S-, -S(O) ２ optionally replaced by - or -(C)=CH-; m is 0, 1, 2, 3, or 4; and each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with 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. Ring AAA is: 【Chemical 1232】 and Ring A is: 【Chemical 1233】 2. The compound of claim 1, wherein:

3. Ring A is: 【Chemical 1234】 or 【Chemical 1235】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R200 is halogen.

4. The TBM has the formula (IIAA'): 【Chemical 1236】 4. The compound of claim 1, wherein the compound has the structure: In formula (IIAA'), when Q is attached to only a single bond, Q is independently selected at each occurrence from -CH- and -N-, or when Q is attached to a double bond, Q is -C=; R １ is hydrogen, C １ ~C ６ Aliphatic, ring 1, -C １ ~C ６ Alkylene-Ring 1 and -Ring 1'-C １ ~C ６ aliphatic; wherein said C １ ~C ６ aliphatic, the ring 1, the C １ ~C ６ Alkylene-ring 1, and the -ring 1'-C １ ~C ６ Each aliphatic independently is —F, —Cl, —Br, —I, and —OR Ｃ optionally substituted with one or more of: R ２Ａ is a covalent bond, C １ ~C １２ alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; １ ~C １２ alkylene, and ring 2A; or R ２Ａ is -C １ ~C １２ Alkylene-Ring 2A-, -Ring 2A-Z ５ -, or -(ring 2A)-Z ５ -(Ring 2A)-, where R ２Ａ -(Ring 2A)-Z ５ -(ring 2A)-, the two rings 2A may be the same or different; １ ~C １２ The alkylene and each of the rings 2A independently represent one or more R Ｋ and optionally substituted with; R ３ is hydrogen and C １ ~C ６ aliphatic, and said C １ ~C ６ Aliphatic optionally contains 1 to 8 heteroatoms independently selected from O, N, and S, wherein the C １ ~C ６ Aliphatic groups are groups that contain one or more R Ｋ and optionally substituted with; Z １ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ２ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ３ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ４ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ５ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 2A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Each R Ｋ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-N(C １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ aliphatic)-C(O)-(C １ ~C ６ aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ aliphatic), -SO ２ (C １ ~C ６ aliphatic), -SO ２ -N(C １ ~C ６ aliphatic) ２ , -S(O)-O(C １ ~C ６ aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ aliphatic) ３ , -CF ３ , —O—CF ３ , C １ ~C ６ an aliphatic group or two R groups bonded to the same carbon or sulfur atom Ｋ the groups optionally taken together form =0; Each R Ｃ are independently hydrogen or an optionally substituted group, and the optionally substituted group is C １ ~C ６ selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; and 【Chemical 1237】 represents the point of attachment to L, The compound or a pharmaceutically acceptable salt thereof.

5. The TBM is represented by formula (IIA'), formula (IIA"), or formula (IIB): 【Chemistry 1242】 【Chemical 1243】 4. The compound of claim 1, wherein the compound has the structure: In Formula (IIA'), Formula (IIA"), or Formula (IIB), when Q is attached to only a single bond, Q is independently selected at each occurrence from -CH- and -N-, or when Q is attached to a double bond, Q is -C=; R １ is hydrogen, C １ ~C ６ Aliphatic, ring 1, -C １ ~C ６ Alkylene-Ring 1 and -Ring 1'-C １ ~C ６ aliphatic; wherein said C １ ~C ６ aliphatic, said C １ ~C ６ Alkylene-ring 1, and the -ring 1'-C １ ~C ６ Each aliphatic independently is —F, —Cl, —Br, —I, and —OR Ｃ optionally substituted with one or more of: R ２Ａ is a covalent bond, C １ ~C １２ alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; １ ~C １２ alkylene, and ring 2A; or R ２Ａ is -C １ ~C １２ Alkylene-Ring 2A-, -Ring 2A-Z ５ -, or -(ring 2A)-Z ５ -(Ring 2A)-, where R ２Ａ -(Ring 2A)-Z ５ -(ring 2A)-, the two rings 2A may be the same or different; １ ~C １２ The alkylene and each of the rings 2A independently represent one or more R Ｋ and optionally substituted with; R ２Ｂ is hydrogen, C １ ~C ６ aliphatic, and ring 2B, or R ２Ｂ is -C １ ~C ６ Alkylene-Ring 2B, -Ring 2B'-C １ ~C ６ Aliphatic, -ring 2B'-Z ５ - Ring 2B, wherein said C １ ~C ６ aliphatic, said C １ ~C ６ alkylene, the ring 2B, and the ring 2B′ each independently represent one or more R Ｋ and optionally substituted with; R ３ is hydrogen and C １ ~C ６ aliphatic, and said C １ ~C ６ Aliphatic optionally contains 1 to 8 heteroatoms independently selected from O, N, and S, wherein the C １ ~C ６ Aliphatic groups are groups that contain one or more R Ｋ and optionally substituted with; Z １ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ２ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ３ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ４ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ５ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 2A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 2B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; and Ring 2B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two thereof; Each R Ｋ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-N(C １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ aliphatic)-C(O)-(C １ ~C ６ aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ aliphatic), -SO ２ (C １ ~C ６ aliphatic), -SO ２ -N(C １ ~C ６ aliphatic) ２ , -S(O)-O(C １ ~C ６ aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ aliphatic) ３ , -CF ３ , —O—CF ３ , C １ ~C ６ an aliphatic group or two R groups bonded to the same carbon or sulfur atom Ｋ the groups optionally taken together form =0; Each R Ｃ are independently hydrogen or an optionally substituted group, and the optionally substituted group is C １ ~C ６ selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; and 【Chemical 1244】 represents the point of attachment to L, The compound or a pharmaceutically acceptable salt thereof.

6. The TBM is represented by formula (IIBB'-4), formula (IIBB'-4-1), formula (IIA'A'-4), or formula (IIA'A'-4-1): [Chemical 1250] 4. The compound of claim 1, wherein the compound has the structure: In formula (IIBB'-4), formula (IIBB'-4-1), formula (IIA'A'-4), and formula (IIA'A'-4-1), R １ is hydrogen, ring 1, -ring 1'-C １ ~C ６ aliphatic, wherein said Ring 1 or said Ring 1'-C １ ~C ６ Aliphatic groups include -F, -Cl, -Br, -I, and -OR Ｃ optionally substituted with one or more of: Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; R ２Ａ is a covalent bond, C １ ~C １２ alkylene, optionally containing 1 to 8 heteroatoms independently selected from O, N, and S; １ ~C １２ alkylene, and ring 2A, wherein said C １ ~C １２ The alkylene and each of the rings 2A may be one or more R Ｋ and optionally substituted with; R ２Ｂ is hydrogen, C １ ~C ６ aliphatic, and ring 2B, wherein said C １ ~C ６ The aliphatic and ring 2B may be one or more R Ｋ and optionally substituted with; Ring 2B is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; R ３ is hydrogen or C １ ~C ３ is aliphatic; Z １ is a covalent bond, -O-, -NR Ｃ -, -C(O)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -N(R Ｃ )C(O)—, and —C(O)N(R Ｃ )—selected from; Z ２ is a covalent bond, -O-, -NR Ｃ -, -C(O)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -N(R Ｃ )C(O)—, and —C(O)N(R Ｃ )—selected from; Z ３ is a covalent bond, -O-, -NR Ｃ -, -C(O)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -N(R Ｃ )C(O)—, and —C(O)N(R Ｃ )—selected from; Z ４ is a covalent bond, -O-, -NR Ｃ -, -C(O)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -N(R Ｃ )C(O)—, and —C(O)N(R Ｃ )—selected from; Each R Ｋ are independently hydrogen, —F, —Cl, —Br, —I, —OH, —O—(C １ ~C ６ aliphatic), -NH ２ , —NH—(C １ ~C ６ aliphatic), -N(C １ ~C ６ aliphatic) ２ , -N(C １ ~C ６ aliphatic) -OH, -N(C １ ~C ６ aliphatic)-O-(C １ ~C ６ aliphatic), -CN, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C １ ~C ６ aliphatic), -C(O)-NH ２ , -C(O)-N(C １ ~C ６ aliphatic) ２ , -N(C １ ~C ６ aliphatic)-C(O)-(C １ ~C ６ aliphatic), -CF ３ , —O—CF ３ , C １ ~C ６ an aliphatic group or two R groups bonded to the same carbon atom Ｋ optionally taken together to form =0; R Ｃ is hydrogen or C １ ~C ６ is aliphatic; and 【Chemistry 1251】 represents the point of attachment to L, The compound or a pharmaceutically acceptable salt thereof.

7. TBM, (a) Formula (IIBB'-3) or Formula (IIA'A'-3): 【Chemistry 1252】 having the structure: (b) Formula (IIBB'-2) or Formula (IIA'A'-2): 【Chemical 1253】 having the structure In formula (IIBB'-2) and formula (IIA'A'-2), R 1 is H, —C(CH 3 ) 2 —CN, 【Chemistry 1254】 is; (c) Formula (II-AB): 【Chemical 1255】 having the structure: (d) Formula (II-AB-I): 【Chemical 1256】 having the structure: (e) Formula (II-AB-II): 【Chemistry 1257】 having the structure: (f) Formula (II-AB-III): 【Chemical 1258】 having the structure: (g) Formula (II-AB-III): 【Chemistry 1259】 or having the structure (h) Formula (II-AB-III): 【Chemical 1260】 7. The compound of claim 6 having the structure: or a pharmaceutically acceptable salt thereof.

8. R １ is hydrogen, ring 1, -ring 1'-C １ ~C ６ aliphatic, wherein said Ring 1 or said Ring 1'-C １ ~C ６ Aliphatic groups include -F, -Cl, -Br, -I, and -OR Ｃ and optionally substituted with one or more of R 2A is selected from a covalent bond, C 1 -C 12 alkylene optionally containing from 1 to 8 heteroatoms independently selected from O, N, and S, and Ring 2A, wherein each of said C 1 -C 12 alkylene and said Ring 2A is optionally substituted with one or more R K ; R 3 is selected from hydrogen and C 1 -C 3 aliphatic, said C 1 -C 3 aliphatic optionally containing 1 to 8 heteroatoms independently selected from O, N, and S, and said C 1 -C 3 aliphatic optionally substituted with one or more R K ; Z 2 is —NH—; Z 2 is a covalent bond; Z 3 is —NH—; Z 4 is a covalent bond, —O—, —C(O)—, —NH—, or —C(O)—N(CH 3 ); Ring 1 is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 1' is an optionally substituted ring selected from phenylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S; Ring 2A is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 3 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S, or a combination of any two thereof; Each R K is independently hydrogen, -F, -Cl, -Br, -I, -OH, -O- (C 1 -C 6 aliphatic), -NH 2 , -NH- (C 1 -C 6 aliphatic), -N (C 1 -C 6 aliphatic) 2 , -N (C 1 -C 6 aliphatic) -OH, -N (C 1 -C 6 aliphatic) aliphatic) -O-(C 1 -C 6 aliphatic), -CN, -C(O)-C 1 -C 6 aliphatic, -CHO, -CO 2 H, -CO 2 (C 1 -C 6 aliphatic), -C(O)-NH 2 , -C(O)-N (C 1 -C 6 aliphatic) 2 , -N(C 1 -C 6 aliphatic)-C(O)-(C 1 to C 6 aliphatic), -CF 3 , -O-CF 3 , a C 1 -C 6 aliphatic group, or two R K s attached to the same carbon atom optionally join together to form =O, or a pharmaceutically acceptable salt thereof.

9. TBM, (a) Formula (IIA'-2-1): 【Chemical 1264】 having the structure In formula (IIA'-2-1), ring X' is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl, or a heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from one or more R Ｋ , substituted as necessary with (b) Formula (IIA'-2-a): 【Chemical 1265】 having the structure (c) Formula (IIA'-2-2): 【Chemical 1266】 In formula (IIA'-2-2), each R K1 is independently hydrogen, halo, C 1 -C 6 aliphatic, halo-substituted C 1 -C 6 aliphatic, or —O—(C 1 -C 6 aliphatic); Ring X″ is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more R K , and n is 0 to 6; (d) Formula (IIA'-2-2a): 【Chemical 1267】 having the structure (e) Formula (IIA'-2-b): 【Chemical 1268】 having the structure (f) Formula (IIA'-2-3): 【Chemical 1269】 having the structure In formula (IIA'-2-3), ring Xa is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl, or a heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more R K . (g) Formula (IIA'-2-3a): 【Chemistry 1270】 having the structure (h) Formula (IIA'-2-4): 【Chemistry 1271】 having the structure In formula (IIA'-2-4), ring X b is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more R K ; or (i) Formula (IIA'-2-1) 【Chemistry 1272】 having the structure The compound of any one of claims 1 to 3, wherein in formula (IIA'-2-1), Y1 and Y1' are each independently an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S.

10. The TBM is represented by formula (IIIAA) or formula (IIIBB): 【Chemical 1273】 4. The compound of claim 1, wherein the compound has the structure: U is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from N, O, and S; V is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from N, O, and S; R ４ は, hydrogen, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (aliphatic), -NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ ,-CN,-C(O)-C １ ~C ６ Aliphatic, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ -C(O)-(C) １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ -S(O)-C １ ~C ６ Aliphatic, -CD ３ -CF ３ ,または-O-CF ３ であり; R ５Ａ is selected from a covalent bond and Ring 5A, wherein Ring 5A is selected from one or more R ８ and optionally substituted with; R ６Ａ is selected from hydrogen, Ring 6A, and -Ring 6A'-Ring 6A, wherein said Ring 6A and said Ring 6A' are independently selected from one or more R ８ and optionally substituted with; R ５Ｂ is selected from hydrogen, Ring 5B, and -Ring 5B'-Ring 5B, wherein said Ring 5B and said Ring 5B' are independently one or more R ８ and optionally substituted with; R ６Ｂ is selected from a covalent bond and Ring 6B, wherein Ring 6B is selected from one or more R ８ and optionally substituted with; Ring 5A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 6A is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6A' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6B is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Z ６ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ７ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ８ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Each R ７ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ Aliphatic) - C(O) - (C １ ~C ６ Aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ , -S(O)-O(C １ ~C ６ Aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ (Aliphatic) ３ -CD ３ -CF ３ ,または-O-CF ３ であり; Each R ８ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ Aliphatic) - C(O) - (C １ ~C ６ Aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ , -S(O)-O(C １ ~C ６ Aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ (Aliphatic) ３ -CD ３ -CF ３ ,または-O-CF ３ であり; Each R Ｃ are independently hydrogen or optionally substituted C １ ~C ６ is an aliphatic group, and 【Chemistry 1274】 represents the point of attachment to L, The compound or a pharmaceutically acceptable salt thereof.

11. The TBM is represented by formula (IIIAA) or formula (IIIBB): 【Chemistry 1275】 4. The compound of claim 1, wherein the compound has the structure: U is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from N, O, and S; V is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from N, O, and S; R ４ は, hydrogen, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (aliphatic), -NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ ,-CN,-C(O)-C １ ~C ６ Aliphatic, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ -C(O)-(C) １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ -S(O)-C １ ~C ６ Aliphatic, -CD ３ -CF ３ ,または-O-CF ３ であり; R ５Ａ is selected from a covalent bond and Ring 5A, wherein Ring 5A is selected from one or more R ８ and optionally substituted with; R ６Ａ is selected from hydrogen, Ring 6A, and -Ring 6A'-Ring 6A, wherein said Ring 6A and said Ring 6A' are independently selected from one or more R ８ and optionally substituted with; R ５Ｂ is selected from hydrogen, Ring 5B, and -Ring 5B'-Ring 5B, wherein said Ring 5B and said Ring 5B' are independently one or more R ８ and optionally substituted with; R ６Ｂ is selected from a covalent bond and Ring 6B, wherein Ring 6B is selected from one or more R ８ and optionally substituted with; Ring 5A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 6A is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6A' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6B is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Z ６ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ７ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ８ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Each R ７ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ Aliphatic) - C(O) - (C １ ~C ６ Aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ , -S(O)-O(C １ ~C ６ Aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ (Aliphatic) ３ -CD ３ -CF ３ ,または-O-CF ３ であり; Each R ８ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ Aliphatic) - C(O) - (C １ ~C ６ Aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ , -S(O)-O(C １ ~C ６ Aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ (Aliphatic) ３ -CD ３ -CF ３ ,または-O-CF ３ であり; Each R Ｃ are independently hydrogen or optionally substituted C １ ~C ６ is an aliphatic group, and 【Chemistry 1276】 represents the point of attachment to L, however, (i) the TBM has the structure of formula (IIIAA), and Z ６ When is —NH—, —Z ６ -U- is 【Chemical 1277】 Instead, (ii) the TBM has the structure of formula (IIIAA), and R ５Ａ is ring 5A, and Z ７ When is —NH—, —Z ６ -V-Z ７ teeth, 【Chemical 1278】 not; and (iii) TBM has the structure of formula (IIIBB), and Z ６ When is —NH—, —V—Z ６ -teeth, 【Chemistry 1279】 Instead, where A, B, and D are independently -C= or -NR ＡＢ - and R ＡＢ is hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR ＡＢ１ R ＡＢ２ , optionally substituted C1-C8 aliphatic, and optionally substituted 3- to 10-membered carbocyclyl, R ＡＢ１ and R ＡＢ２ are independently hydrogen, optionally substituted C １ ~C ８ Aliphatic, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ alkynyl, optionally substituted 3- to 10-membered carbocyclyl, and optionally substituted 4- to 10-membered heterocyclyl, or R ＡＢ１ and R ＡＢ２ together with the atom or atoms to which they are attached form a 3- to 20-membered carbocyclyl ring or a 4- to 20-membered heterocyclyl ring; The compound or a pharmaceutically acceptable salt thereof.

12. The TBM is represented by formula (IIIA) or formula (IIIB): 【Chemistry 1280】 4. The compound of claim 1, wherein the compound has the structure: In formula (IIIA) and formula (IIIB), Q' is selected from -CH= and -N=; R ４ は, hydrogen, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (aliphatic), -NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ ,-CN,-C(O)-C １ ~C ６ Aliphatic, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ -C(O)-(C) １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ -S(O)-C １ ~C ６ Aliphatic, -CD ３ -CF ３ ,または-O-CF ３ であり; R ５Ａ is selected from a covalent bond and Ring 5A, wherein Ring 5A is selected from one or more R ７ and optionally substituted with; R ６Ａ is selected from hydrogen, Ring 6A, and -Ring 6A'-Ring 6A, wherein said Ring 6A and said Ring 6A' are independently selected from one or more R ７ and optionally substituted with; R ５Ｂ is selected from hydrogen, Ring 5B, and -Ring 5B'-Ring 5B, wherein said Ring 5B and said Ring 5B' are independently one or more R ７ and optionally substituted with; R ６Ｂ is selected from a covalent bond and Ring 6B, wherein Ring 6B is selected from one or more R ７ and optionally substituted with; Ring 5A is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Ring 6A is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6A' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B is an optionally substituted ring selected from phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 5B' is an optionally substituted ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 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 N, O, and S, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from N, O, and S; Ring 6B is selected from the group consisting of phenylenyl, 8- to 10-membered bicyclic arylenyl, 3- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from N, O, and S, an optionally substituted ring selected from a saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from N, O, and S, a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from N, O, and S, and an 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from N, O, and S, or a combination of any two of these; Z ６ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ７ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Z ８ is a covalent bond, -O-, -NR Ｃ -, -S-, -C(O)-, -C(S)-, -CR Ｃ ２ -, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—; Each R ７ は independent して, water element, -F, -Cl, -Br, -I, -OH, -O- (C １ ~C ６ (Aliphatic), -NO, -NO ２ -NO ３ -O-NO, -N ３ 、-NH ２ ,-NH-(C １ ~C ６ Aliphatic), -N (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) ３ ＋ 、-N(C １ ~C ６ (Aliphatic) -OH, -ON (C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -O- (C １ ~C ６ Aliphatic), -CN, -NC, -C(O)-C １ ~C ６ Aliphatic, -CHO, -CO ２ H, -CO ２ (C) １ ~C ６ Aliphatic), -C(O)-S-(C １ ~C ６ Aliphatic), -O-C(O)-H, -O-C(O)-(C １ ~C ６ Aliphatic), -S-C(O)-(C １ ~C ６ Aliphatic), -C(O)-NH ２ , -C(O)-NH(C １ ~C ６ Aliphatic), -C(O)-N(C) １ ~C ６ (Aliphatic) ２ ,-C(O)-NHNH ２ ,-O-C(O)-NHNH ２ -C(S)-NH ２ , -C(S)-N(C １ ~C ６ (Aliphatic) ２ 、-N(C １ ~C ６ (Aliphatic) -CHO, -N (C １ ~C ６ Aliphatic) - C(O) - (C １ ~C ６ Aliphatic), -SCN, -NCS, -NSO, -SS (C １ ~C ６ (Aliphatic), -SO ２ (C) １ ~C ６ (Aliphatic), -SO ２ -N(C) １ ~C ６ (Aliphatic) ２ , -S(O)-O(C １ ~C ６ Aliphatic), -S(O)-C １ ~C ６ Aliphatic, -Si(C １ ~C ６ (Aliphatic) ３ -CD ３ -CF ３ ,または-O-CF ３ であり; Each R Ｃ are independently hydrogen or optionally substituted C １ ~C ６ is an aliphatic group, and 【Chemistry 1281】 represents the point of attachment to L, The compound or a pharmaceutically acceptable salt thereof.

13. TBM, (a) Formula (IIIA-3-1) or Formula (IIIA-3-2): 【Chemical 1286】 In formula (IIIA-3-1) and formula (IIIA-3-2), Ring X ＡＡ is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S; (b) Formula (IIIA-3-1-1) or Formula (IIIA-3-2-1): 【Chemistry 1287】 In formula (IIIA-3-1-1) and formula (IIIA-3-2-1), Ring X AA is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S; R 4aa is —CH 3 , CD 3 , —CH 2 CH 3 , or 【Chemical 1288】 That is, (c) Formula (IIIA-3-1-2) or Formula (IIIA-3-2-2): 【Chemistry 1289】 In formula (IIIA-3-1-2) or formula (IIIA-3-2-2), Ring X AA is an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S; or (d) Formula (IIIA-3): 【Chemistry 1290】 11. The compound of claim 10 having the structure: or a pharmaceutically acceptable salt thereof.

14. Z ７ is a covalent bond, -NR Ｃ -, -C(O)-, -NR Ｃ C(O)-, -C(O)NR Ｃ - and -NR Ｃ C(O)NR Ｃ - is selected from, Z 8 is selected from a covalent bond, —C(R C 2 )—, —NR C —, —C(O)—, and —C(O)NR C —; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R 5A is a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from N, O, and S.

15. The TBM is represented by formula (IIIA-3-3): 【Chemistry 1292】 having the structure 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R 6A is hydrogen or an optionally substituted ring selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S.

16. L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched chain C １ ~C ２０ an alkylene chain, wherein 0 to 6 methylene units of L are independently -Cy-, -O-, -NR Ｃ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -N(R Ｃ ) S (O) ２ -, -S(O) ２ N (R Ｃ ) -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ )C(O)O—, and combinations thereof; wherein -Cy- in each occurrence is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from an 11- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each R Ｃ is independently in each occurrence hydrogen or an optionally substituted group, and the optionally substituted group is C １ ~C ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and combinations thereof.

17. 0 to 5 methylene units of L independently represent -Cy-, -O-, or -NR Ｃ -, -N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-OC(O)N(R Ｃ )-, and -N(R Ｃ 4. The compound of claim 1, wherein the substituted aryl group is substituted by aryl, ...

18. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein each -Cy- is independently an optionally substituted divalent ring selected from phenylenyl, a 4- to 6-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 10-membered saturated or partially unsaturated spirocarbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

19. L is: 【Chemical 1306】 and Here, Q ４ When Q is bonded only to a single bond, each Q ４ is independently selected from —CH— and —N—, or Q ４ When Q is attached to a double bond, ４ is ═CH— or ═N—; 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

20. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds depicted in Table 1.

21. A pharmaceutical composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

22. A composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for treating a TYK2-mediated disorder, disease, or condition in a subject in need thereof.

23. 23. The composition or pharmaceutical composition of claim 22, wherein the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder.

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